bims-imicid 2024-07-14 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–07–14
fifty papers selected by
Dylan Ryan, University of Cambridge

4-Octyl itaconate blocks GSDMB-mediated pyroptosis and restricts inflammation by inactivating granzyme A.
CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism.
Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human macrophages and blunt glycolysis in response to antigenic stimuli.
Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.
Skin deep: Epithelial cell metabolism and chronic skin inflammation.
Pseudomonas aeruginosa impairs mitochondrial function and metabolism during infection of corneal epithelial cells.
Metabolic changes in Toxoplasma gondii-infected host cells measured by autofluorescence imaging.
Immunoregulation: the interplay between metabolism and redox homeostasis.
Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.
Sirtuin 2 regulates neutrophil functions through NAD+ synthesis pathway in virus infection.
Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.
Metabolic dynamics in psoriatic epidermis: Enhanced glucose and lactate uptake, glycolytic pathway and TCA cycle dynamics.
Rv0547c, a functional oxidoreductase, supports Mycobacterium tuberculosis persistence by reprogramming host mitochondrial fatty acid metabolism.
The innate memory response of macrophages to Mycobacterium tuberculosis is shaped by the nature of the antigenic stimuli.
Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.
Metabolic flux in macrophages in obesity and type-2 diabetes.
Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections.
Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.
A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.
Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages.
Physiologic medium renders human iPSC-derived macrophages permissive for M. tuberculosis by rewiring organelle function and metabolism.
MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming.
Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming.
Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis.
Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.
Seeing the unseen: illuminating Toxoplasma gondii's metabolic manipulation.
Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.
Dietary pectin and inulin: a promising adjuvant supplement for collagen-induced arthritis through gut microbiome restoration and CD4+ T cell reconstitution.
Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer.
12,13-diHOME Promotes Inflammatory Macrophages and Epigenetically Modifies Their Capacity to Respond to Microbes and Allergens.
Aconitate decarboxylase (ACOD1) has found a disease.
IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation.
Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.
Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.
Metabolic profiling of single cells by exploiting NADH and FAD fluorescence via flow cytometry.
The anti-inflammatory effects of itaconate and its derivatives in neurological disorders.
Bacterial reprogramming of tick metabolism impacts vector fitness and susceptibility to infection.
Alpha-melanocyte-stimulating hormone contributes to an anti-inflammatory response to lipopolysaccharide in male C57BL6/J mice.
Immune cells phenotype and bioenergetic measures in CD4+ T cells differ between high and low feed efficient dairy cows.
Metformin as a therapeutic agent for obesity-associated immune dysfunction.
ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.
Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway.
TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.
Derivative spectrophotometry-assisted determination of tryptophan metabolites emerges host and intestinal flora dysregulations during sepsis.
Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.
Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.
Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV.
α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.
15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.
Kidney targeting and modulating macrophage polarization through AMPK signaling: Therapeutic mechanism of berberine in uric acid nephropathy.

Cell Prolif. 2024 Jul 09. e13711

4-Octyl itaconate blocks GSDMB-mediated pyroptosis and restricts inflammation by inactivating granzyme A.

Wenbin Gong, Hangyu Fu, Kui Yang, Tao Zheng, Kun Guo, Wei Zhao.

GSDMB-mediated pyroptosis facilitates a pro-inflammatory immune microenvironment and needs to be tightly regulated to avoid excessive inflammation. Here, we provide evidence that itaconate and its cell-permeable derivative 4-octyl itaconate (4-OI) can significantly inhibit GSDMB-rendered pyroptotic activity independent of Nrf2. 4-OI interferes proteolytic process of GSDMB by directly modifying Cys54, Cys148 and Ser212 on granzyme A (GrzA), a serine protease that site-specifically cleaves the inter-domain linker of GSDMB, instead of interaction with GSDMB, thereby blocking pyroptosis and exerts anti-inflammatory effects. Moreover, 4-OI alleviates inflammation by suppressing GSDMB-induced pyroptotic cell death during acute colitis models in intestinal epithelial GSDMB conditional transgenic mice. Our data expand the role of 4-OI as a crucial immunometabolic derivative that regulates innate immunity and inflammation through a newly identified posttranslational modification, and targeting of pyroptosis by 4-OI therefore holds potent therapeutic potential for primarily inflammatory and/or autoimmune diseases.

DOI: https://doi.org/10.1111/cpr.13711
Theranostics. 2024 ;14(10): 3793-3809

CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism.

Jingzeng Wang, Wenlong Jia, Xi Zhou, Zhibo Ma, Jing Liu, Peixiang Lan.

  Rationale: CD8+ T cells undergo a series of metabolic reprogramming processes during their activation and proliferation, including increased glycolysis, decreased aerobic oxidation of sugars, increased amino acid metabolism and increased protein synthesis. However, it is still unclear what factors regulate these metabolic reprogramming processes in CD8+ T cells in the tumor immune microenvironment. Methods: T cell chromobox protein 4 (CBX4) knock-out mice models were used to determine the role of CBX4 in CD8+ T cells on the tumor immune microenvironment and tumor progression. Flow cytometry, Cut-Tag qPCR, Chip-seq, immunoprecipitation, metabolite detection, lentivirus infection and adoptive T cells transfer were performed to explore the underlying mechanisms of CBX4 knock-out in promoting CD8+ T cell activation and inhibiting tumor growth. Results: We found that CBX4 expression was induced in tumor-infiltrating CD8+ T cells and inhibited CD8+ T cell function by regulating glucose metabolism in tumor tissue. Mechanistically, CBX4 increases the expression of the metabolism-associated molecule aldolase B (Aldob) through sumoylation of trans-acting transcription factor 1 (SP1) and Krüppel-like factor 3 (KLF3). In addition, Aldob inhibits glycolysis and ATP synthesis in T cells by reducing the phosphorylation of the serine/threonine protein kinase (Akt) and ultimately suppresses CD8+ T cell function. Significantly, knocking out CBX4 may improve the efficacy of anti-PD-1 therapy by enhancing the function of CD8+ T cells in the tumor microenvironment. Conclusion: CBX4 is involved in CD8+ T cell metabolic reprogramming and functional persistence in tumor tissues, and serves as an inhibitor in CD8+ T cells' glycolysis and effector function.

Keywords:  Aldob; CBX4; CD8+ T cell; anti-tumor; glucose metabolism

DOI:  https://doi.org/10.7150/thno.95748
Eur J Immunol. 2024 Jul 11. e2451032

Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human macrophages and blunt glycolysis in response to antigenic stimuli.

Gina Leisching, Anjali Yennemadi, Karl Gogan, Joseph Keane.

  The impact of chronic exposure to type I interferons (IFN)-α2a, 2b, and β on macrophage metabolism, intimately linked to macrophage function, is not well understood. This study assesses the nuanced host responses induced by type I IFN cytokines, offering insights into potential therapeutic approaches in diseases associated with these cytokines. Employing a combination of transcriptional profiling and real-time functional analysis, we delineated metabolic reprogramming in response to chronic IFN exposure. Our results reveal distinct transcriptional metabolic profiles between macrophages chronically exposed to IFN-α and IFN-β. IFN-β significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFN-α2b decreased parameters of mitochondrial fitness and induced a shift toward glutamine oxidation. Assessing the ability of macrophages to induce glycolysis in response to antigenic stimuli (LPS and iH37Rv), we found that chronic exposure to all IFN subtypes limited glycolytic induction. This study addresses a critical oversight in the literature, where individual roles of IFN subtypes are frequently amalgamated and lack distinction. These findings not only provide novel insights into the divergent effects of IFN-α2a, α2b, and β on macrophage metabolism but also highlight their potential implications for developing targeted therapeutic strategies.

Keywords:  Glycolysis; LPS; M. tuberculosis; Macrophage; Metabolism; Oxidative phosphorylation; Transcriptomics; Type I interferons

DOI:  https://doi.org/10.1002/eji.202451032
PLoS Pathog. 2024 Jul 08. 20(7): e1011909

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Adam Hafner, Noah Meurs, Ari Garner, Elaine Azar, Aditya Kannan, Karla D Passalacqua, Deepak Nagrath, Christiane E Wobus.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.

DOI: https://doi.org/10.1371/journal.ppat.1011909
Immunity. 2024 Jul 09. pii: S1074-7613(24)00310-8. [Epub ahead of print]57(7): 1451-1453

Skin deep: Epithelial cell metabolism and chronic skin inflammation.

Eliana R Solis, Julie M Jameson.

Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.

DOI: https://doi.org/10.1016/j.immuni.2024.06.004
bioRxiv. 2024 Jun 25. pii: 2024.06.24.600521. [Epub ahead of print]

Pseudomonas aeruginosa impairs mitochondrial function and metabolism during infection of corneal epithelial cells.

Rajalakshmy Ayilam Ramachandran, Joelle T Abdallah, Mahad Rehman, Hamid Baniasadi, Abigail M Blanton, Santiago Vizcaino, Danielle M Robertson.

Pseudomonas aeruginosa (PA) is a gram-negative opportunistic pathogen that can infect the cornea as a result of trauma or contact lens wear. In addition to their known energy producing role, mitochondria are important mediators of immune signaling and host defense. While certain pathogens have developed strategies to evade host defenses by modulating host mitochondrial dynamics and metabolism, the ability of PA to harness host cell mitochondria during corneal infection is unknown. Using a combination of biochemical and imaging techniques, we show that PA infection of corneal epithelial cells induced mitochondrial fission in a DRP1-dependent manner that preceded PINK1/Parkin and FUNDC1-mediated mitophagy. PA also impaired NADH-linked respiration through a reduction in complex 1. This corresponded to a decrease in metabolic pathways related to glycolysis and the TCA cycle. Metabolomics analysis further demonstrated an upregulation of the pentose phosphate pathway, arginine, purine, and pyrimidine metabolism in PA infected cells. These pathways may provide a key source of nucleotides, amino acids, and nitrogen for both the host cell and PA, in addition to antioxidant functions. Following treatment with gentamicin to kill all extracellular bacteria, metabolic flux analysis showed that corneal epithelial cells were able to restore mitochondrial function despite the continued presence of intracellular PA. Taken together, these data demonstrate that mitochondrial dysfunction and metabolic rewiring in host cells is triggered by extracellular PA, but once inside, PA requires healthy mitochondria to ensure host cell survival.

DOI: https://doi.org/10.1101/2024.06.24.600521
mBio. 2024 Jul 08. e0072724

Metabolic changes in Toxoplasma gondii-infected host cells measured by autofluorescence imaging.

Gina M Gallego-López, Emmanuel Contreras Guzman, Danielle E Desa, Laura J Knoll, Melissa C Skala.

  Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular parasite that infects warm-blooded vertebrates across the world. In humans, seropositivity rates of T. gondii range from 10% to 90% across communities. Despite its prevalence, few studies address how T. gondii infection changes the metabolism of host cells. In this study, we investigate how T. gondii manipulates the host cell metabolic environment by monitoring the metabolic response over time using noninvasive autofluorescence lifetime imaging of single cells, metabolite analysis, extracellular flux analysis, and reactive oxygen species (ROS) production. Autofluorescence lifetime imaging indicates that infected host cells become more oxidized and have an increased proportion of bound NAD(P)H compared to uninfected controls. Over time, infected cells also show decreases in levels of intracellular glucose and lactate, increases in oxygen consumption, and variability in ROS production. We further examined changes associated with the pre-invasion "kiss and spit" process using autofluorescence lifetime imaging, which also showed a more oxidized host cell with an increased proportion of bound NAD(P)H over 48 hours compared to uninfected controls, suggesting that metabolic changes in host cells are induced by T. gondii kiss and spit even without invasion.IMPORTANCEThis study sheds light on previously unexplored changes in host cell metabolism induced by T. gondii infection using noninvasive, label-free autofluorescence imaging. In this study, we use optical metabolic imaging (OMI) to measure the optical redox ratio (ORR) in conjunction with fluorescence lifetime imaging microscopy (FLIM) to noninvasively monitor single host cell response to T. gondii infection over 48 hours. Collectively, our results affirm the value of using autofluorescence lifetime imaging to noninvasively monitor metabolic changes in host cells over the time course of a microbial infection. Understanding this metabolic relationship between the host cell and the parasite could uncover new treatment and prevention options for T. gondii infections worldwide.

Keywords:  NAD(P)H-binding enzymes; Toxoplasma gondii; host cell metabolism; optical metabolic imaging (OMI); reactive oxygen species; redox biology

DOI:  https://doi.org/10.1128/mbio.00727-24
Front Transplant. 2023 ;2 1283275

Immunoregulation: the interplay between metabolism and redox homeostasis.

E Perpiñán, A Sanchez-Fueyo, N Safinia.

  Regulatory T cells are fundamental for the induction and maintenance of immune homeostasis, with their dysfunction resulting in uncontrolled immune responses and tissue destruction predisposing to autoimmunity, transplant rejection and several inflammatory and metabolic disorders. Recent discoveries have demonstrated that metabolic processes and mitochondrial function are critical for the appropriate functioning of these cells in health, with their metabolic adaptation, influenced by microenvironmental factors, seen in several pathological processes. Upon activation regulatory T cells rearrange their oxidation-reduction (redox) system, which in turn supports their metabolic reprogramming, adding a layer of complexity to our understanding of cellular metabolism. Here we review the literature surrounding redox homeostasis and metabolism of regulatory T cells to highlight new mechanistic insights of these interlinked pathways in immune regulation.

Keywords:  NRF2; anti-oxidants; mTOR; reactive oxygen species; regulatory T cells

DOI:  https://doi.org/10.3389/frtra.2023.1283275
Am J Physiol Cell Physiol. 2024 Jul 09.

Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.

Alan J Mouton, Nikaela M Aitken, Jemylle G Morato, Jussara M do Carmo, Alexandre A da Silva, Ana C Omoto, Xuan Li, Zhen Wang, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Joshua K Stanford, Jordan A Brown, John E Hall.

  Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved LV function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI, and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism.

Keywords:  cardiac remodeling; glutamine; heart failure; immunometabolism; macrophage

DOI:  https://doi.org/10.1152/ajpcell.00272.2024
iScience. 2024 Jul 19. 27(7): 110184

Sirtuin 2 regulates neutrophil functions through NAD+ synthesis pathway in virus infection.

Zhiyuan Zhang, Qiuli Yang, Yingjie Dong, Likun Wang, Ruiying Niu, Jingxuan Xia, Yujing Bi, Guangwei Liu.

  Neutrophils play an important role in antiviral immunity, but the underlying mechanisms remain unclear. Here, we found that SIRT2 deficiency inhibited the infiltration of neutrophils, as well as the secretion of inflammatory cytokines and the formation of neutrophil extracellular traps (NETs), ameliorating disease symptoms during acute respiratory virus infection. Mechanistically, SIRT2 deficiency upregulates quinolinic acid (QA)-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) and leads to expression of quinolinate phosphoribosyltransferase (QPRT), which promotes the synthesis of QA for NAD+ and limits viral infection when de novo NAD+ synthesis is blocked. Tryptophan-2,3-oxygenase expressed in epithelial cells metabolizes tryptophan to produce kynurenine and 3-hydroxyaminobenzoic acid, which is a source of intracellular QA in neutrophils. Thus, our findings reveal a previously unrecognized QPRT-mediated switch in NAD+ metabolism by exploiting neutrophil-derived QA as an alternative source of replenishing intracellular NAD+ pools induced by SIRT2 to regulate neutrophil functions during virus infection, with implications for future immunotherapy approaches.

Keywords:  cell biology; immunity; molecular biology; virology

DOI:  https://doi.org/10.1016/j.isci.2024.110184
Immune Netw. 2024 Jun;24(3): e26

Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.

Jisu Kim, Jee Yeon Choi, Hyeyoung Min, Kwang Woo Hwang.

  Recent advancements in various technologies have shed light on the critical role of metabolism in immune cells, paving the way for innovative disease treatment strategies through immunometabolism modulation. This review emphasizes the glucose metabolism of myeloid-derived suppressor cells (MDSCs), an emerging pivotal immunosuppressive factor especially within the tumor microenvironment. MDSCs, an immature and heterogeneous myeloid cell population, act as a double-edged sword by exacerbating tumors or mitigating inflammatory diseases through their immune-suppressive functions. Numerous recent studies have centered on glycolysis of MDSC, investigating the regulation of altered glycolytic pathways to manage diseases. However, the specific changes in MDSC glycolysis and their exact functions continue to be areas of ongoing discussion yet. In this paper, we review a range of current findings, including the latest research on the alteration of glycolysis in MDSCs, the consequential functional alterations in these cells, and the outcomes of attempts to modulate MDSC functions by regulating glycolysis. Ultimately, we will provide insights into whether these research efforts could be translated into clinical applications.

Keywords:  Glycolysis; Immunomodulation; Metabolic reprogramming; Myeloid-derived suppressor cell

DOI:  https://doi.org/10.4110/in.2024.24.e26
Exp Dermatol. 2024 Jul;33(7): e15127

Metabolic dynamics in psoriatic epidermis: Enhanced glucose and lactate uptake, glycolytic pathway and TCA cycle dynamics.

Satoshi Nakamizo, Hiromi Doi, Kenji Kabashima.



Keywords:  GLUT1; MCT1; keratinocyte; psoriasis

DOI:  https://doi.org/10.1111/exd.15127
Mitochondrion. 2024 Jul 08. pii: S1567-7249(24)00089-8. [Epub ahead of print] 101931

Rv0547c, a functional oxidoreductase, supports Mycobacterium tuberculosis persistence by reprogramming host mitochondrial fatty acid metabolism.

Jayashankar Medikonda, Nandini Wankar, Suman Asalla, Sufi O Raja, Sriram Yandrapally, Haneesh Jindal, Anushka Agarwal, Chitrakshi Pant, Shasi V Kalivendi, Harish Kumar Dubey, Krishnaveni Mohareer, Akash Gulyani, Sharmistha Banerjee.

  Mycobacterium tuberculosis (Mtb) successfully thrives in the host by adjusting its metabolism and manipulating the host environment. In this study, we investigated the role of Rv0547c, a protein that carries mitochondria-targeting sequence (MTS), in mycobacterial persistence. We show that Rv0547c is a functional oxidoreductase that targets host-cell mitochondria. Interestingly, the localization of Rv0547c to mitochondria was independent of the predicted MTS but depended on specific arginine residues at the N- and C-terminals. As compared to the mitochondria-localization defective mutant, Rv0547c-2SDM, wild-type Rv0547c increased mitochondrial membrane fluidity and spare respiratory capacity. To comprehend the possible reason, comparative lipidomics was performed that revealed a reduced variability of long-chain and very long-chain fatty acids as well as altered levels of phosphatidylcholine and phosphatidylinositol class of lipids upon expression of Rv0547c, explaining the increased membrane fluidity. Additionally, the over representation of propionate metabolism and β-oxidation intermediates in Rv0547c-targeted mitochondrial fractions indicated altered fatty acid metabolism, which corroborated with changes in oxygen consumption rate (OCR) upon etomoxir treatment in HEK293T cells transiently expressing Rv0547c, resulting in enhanced mitochondrial fatty acid oxidation capacity. Furthermore, Mycobacterium smegmatis over expressing Rv0547c showed increased persistence during infection of THP-1 macrophages, which correlated with its increased expression in Mtb during oxidative and nutrient starvation stresses. This study identified for the first time an Mtb protein that alters mitochondrial metabolism and aids in survival in host macrophages by altering fatty acid metabolism to its benefit and, at the same time increases mitochondrial spare respiratory capacity to mitigate infection stresses and maintain cell viability.

Keywords:  FAO; Lipid metabolism; Lipid profiling; Metabolic flux; Mycobacterium tuberculosis; Oxidoreductase; Rv0547c

DOI:  https://doi.org/10.1016/j.mito.2024.101931
Microbiol Spectr. 2024 Jul 09. e0047324

The innate memory response of macrophages to Mycobacterium tuberculosis is shaped by the nature of the antigenic stimuli.

Ranjeet Kumar, Afsal Kolloli, Pooja Singh, Lanbo Shi, Andreas Kupz, Selvakumar Subbian.

  Innate immune cells, such as macrophages, mount an immune response upon exposure to antigens and pathogens. Emerging evidence shows that macrophages exposed to an antigen can generate a "memory-like" response (a.k.a. trained immunity), which confers a non-specific and enhanced response upon subsequent stimulation with a second antigen/microbe. This trained immunity has been implicated in the enhanced response of macrophages against several invading pathogens. However, the association between the nature of the antigen and the corresponding immune correlate of elicited trained immunity is not fully understood. Similarly, the response of macrophages trained and restimulated with homologous stimulants to subsequent infection by pathogenic Mycobacterium tuberculosis (Mtb) remains unexplored. Here, we report the immune and metabolic profiles of trained immunity in human THP-1-derived macrophages after homologous training and restimulation with BCG, LPS, purified protein Derivative (PPD), heat-killed Mtb strains HN878 (hk-HN), and CDC1551 (hk-CDC). Furthermore, the impact of training on the autophagic and antimicrobial responses of macrophages with or without subsequent infection by clinical Mtb isolates HN878 and CDC1551 was evaluated. Results show that repeated stimulation of macrophages with different antigens displays distinct pro-inflammatory, metabolic, antimicrobial, and autophagy induction profiles. These macrophages also induce a differential antimicrobial response upon infection with clinical Mtb HN878 and CDC1551 isolates. A significantly reduced intracellular bacterial load was noted in the stimulated macrophages, which was augmented by the addition of rapamycin, an autophagy inducer. These observations suggest that the nature of the antigen and the mode of stimulation shape the magnitude and breadth of macrophage innate memory response, which impacts subsequent response to Mtb infection.
IMPORTANCE: Trained immunity (a.k.a. innate memory response) is a novel concept that has been rapidly emerging as a mechanism underpinning the non-specific immunity of innate immune cells, such as macrophages. However, the association between the nature of the stimuli and the corresponding immune correlate of trained immunity is not fully understood. Similarly, the kinetics of immunological and metabolic characteristics of macrophages upon "training" by the same antigen as primary and secondary stimuli (homologous stimulation) are not fully characterized. Furthermore, the ability of antigens such as purified protein derivative (PPD) and heat-killed-Mtb to induce trained immunity remains unknown. Similarly, the response of macrophages primed and trained by homologous stimulants to subsequent infection by pathogenic Mtb is yet to be reported. In this study, we evaluated the hypothesis that the nature of the stimuli impacts the depth and breadth of trained immunity in macrophages, which differentially affects their response to Mtb infection.

Keywords:  autophagy; immunometabolism; inflammation; trained immunity; tuberculosis

DOI:  https://doi.org/10.1128/spectrum.00473-24
Front Immunol. 2024 ;15 1410832

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.

Aleksandr E Vendrov, Andrey Lozhkin, Takayuki Hayami, Julia Levin, Jamille Silveira Fernandes Chamon, Ahmed Abdel-Latif, Marschall S Runge, Nageswara R Madamanchi.

   Introduction: Aging increases the risk of atherosclerotic vascular disease and its complications. Macrophages are pivotal in the pathogenesis of vascular aging, driving inflammation and atherosclerosis progression. NOX4 (NADPH oxidase 4) expression increases with age, correlating with mitochondrial dysfunction, inflammation, and atherosclerosis. We hypothesized that the NOX4-dependent mitochondrial oxidative stress promotes aging-associated atherosclerosis progression by causing metabolic dysfunction and inflammatory phenotype switch in macrophages.
Methods: We studied atherosclerotic lesion morphology and macrophage phenotype in young (5-month-old) and aged (16-month-old) Nox4 -/-/Apoe -/- and Apoe -/- mice fed Western diet.
Results: Young Nox4-/-/Apoe-/- and Apoe-/- mice had comparable aortic and brachiocephalic artery atherosclerotic lesion cross-sectional areas. Aged mice showed significantly increased lesion area compared with young mice. Aged Nox4-/-/Apoe-/- had significantly lower lesion areas than Apoe-/- mice. Compared with Apoe-/- mice, atherosclerotic lesions in aged Nox4-/-/Apoe-/- showed reduced cellular and mitochondrial ROS and oxidative DNA damage, lower necrotic core area, higher collagen content, and decreased inflammatory cytokine expression. Immunofluorescence and flow cytometry analysis revealed that aged Apoe-/- mice had a higher percentage of classically activated pro-inflammatory macrophages (CD38+CD80+) in the lesions. Aged Nox4-/-/Apoe-/- mice had a significantly higher proportion of alternatively activated pro-resolving macrophages (EGR2+/CD163+CD206+) in the lesions, with an increased CD38+/EGR2+ cell ratio compared with Apoe-/- mice. Mitochondrial respiration assessment revealed impaired oxidative phosphorylation and increased glycolytic ATP production in macrophages from aged Apoe-/- mice. In contrast, macrophages from Nox4-/-/Apoe-/- mice were less glycolytic and more aerobic, with preserved basal and maximal respiration and mitochondrial ATP production. Macrophages from Nox4-/-/Apoe-/- mice also had lower mitochondrial ROS levels and reduced IL1β secretion; flow cytometry analysis showed fewer CD38+ cells after IFNγ+LPS treatment and more EGR2+ cells after IL4 treatment than in Apoe-/- macrophages. In aged Apoe-/- mice, inhibition of NOX4 activity using GKT137831 significantly reduced macrophage mitochondrial ROS and improved mitochondrial function, resulting in decreased CD68+CD80+ and increased CD163+CD206+ lesion macrophage proportion and attenuated atherosclerosis.
Discussion: Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity.

Keywords:  NOX4 NADPH oxidase; aging; atherosclerosis; macrophages; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fimmu.2024.1410832
J Pharm Pharm Sci. 2024 ;27 13210

Metabolic flux in macrophages in obesity and type-2 diabetes.

Angela Wong, Qiuyu Sun, Ismail Ibrahim Latif, Qutuba G Karwi.

  Recent literature extensively investigates the crucial role of energy metabolism in determining the inflammatory response and polarization status of macrophages. This rapidly expanding area of research highlights the importance of understanding the link between energy metabolism and macrophage function. The metabolic pathways in macrophages are intricate and interdependent, and they can affect the polarization of macrophages. Previous studies suggested that glucose flux through cytosolic glycolysis is necessary to trigger pro-inflammatory phenotypes of macrophages, and fatty acid oxidation is crucial to support anti-inflammatory responses. However, recent studies demonstrated that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully understood yet. How the metabolic flux through different metabolic pathways (glycolysis, glucose oxidation, fatty acid oxidation, ketone oxidation, and amino acid oxidation) is altered by obesity- and type 2 diabetes (T2D)-associated insulin resistance is also not fully defined. This mini-review focuses on the impact of insulin resistance in obesity and T2D on the metabolic flux through the main metabolic pathways in macrophages, which might be linked to changes in their inflammatory responses. We closely evaluated the experimental studies and methodologies used in the published research and highlighted priority research areas for future investigations.

Keywords:  amino acids; fatty acids; glucose; ketones; macrophage; metabolism; obesity; type-2 diabetes

DOI:  https://doi.org/10.3389/jpps.2024.13210
Cell Rep. 2024 Jul 10. pii: S2211-1247(24)00815-5. [Epub ahead of print]43(7): 114486

Glucose transporter 1 is essential for the resolution of methicillin-resistant S. aureus skin and soft tissue infections.

Srijon K Banerjee, Lance R Thurlow, Kartik Kannan, Anthony R Richardson.

  Skin/soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) pose a major healthcare burden. Distinct inflammatory and resolution phases comprise the host immune response to SSTIs. Resolution is a myeloid PPARγ-dependent anti-inflammatory phase that is essential for the clearance of MRSA. However, the signals activating PPARγ to induce resolution remain unknown. Here, we demonstrate that myeloid glucose transporter 1 (GLUT-1) is essential for the onset of resolution. MRSA-challenged macrophages are unsuccessful in generating an oxidative burst or immune radicals in the absence of GLUT-1 due to a reduction in the cellular NADPH pool. This translates in vivo as a significant reduction in lipid peroxidation products required for the activation of PPARγ in MRSA-infected mice lacking myeloid GLUT-1. Chemical induction of PPARγ during infection circumvents this GLUT-1 requirement and improves resolution. Thus, GLUT-1-dependent oxidative burst is essential for the activation of PPARγ and subsequent resolution of SSTIs.

Keywords:  CP: Metabolism; CP: Microbiology; aureus; immunometabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114486
bioRxiv. 2024 Jun 28. pii: 2024.06.23.600101. [Epub ahead of print]

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.

Wesley H Godfrey, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Nagireddy Putluri, Michael D Kornberg.

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.

DOI: https://doi.org/10.1101/2024.06.23.600101
Cell Metab. 2024 Jul 03. pii: S1550-4131(24)00235-3. [Epub ahead of print]

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

Lynn Bonetti, Veronika Horkova, Melanie Grusdat, Joseph Longworth, Luana Guerra, Henry Kurniawan, Davide G Franchina, Leticia Soriano-Baguet, Carole Binsfeld, Charlène Verschueren, Sabine Spath, Anouk Ewen, Eric Koncina, Jean-Jacques Gérardy, Takumi Kobayashi, Catherine Dostert, Sophie Farinelle, Janika Härm, Yu-Tong Fan, Ying Chen, Isaac S Harris, Philipp A Lang, Vasilis Vasiliou, Ari Waisman, Elisabeth Letellier, Burkhard Becher, Michel Mittelbronn, Dirk Brenner.

  The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Keywords:  C. rodentium; Gclc; IL-22; ROS; T cells; Th17 cells; colitis; gastrointestinal infection; glutathione; intestinal barrier; mitochondrial function

DOI:  https://doi.org/10.1016/j.cmet.2024.06.010
Acta Pharmacol Sin. 2024 Jul 10.

Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages.

De-Chong Zheng, Jia-Qin Hu, Chu-Tian Mai, Li Huang, Hua Zhou, Li-Li Yu, Ying Xie.

  Liver X receptors (LXRs) which link lipid metabolism and inflammation, were overexpressed in experimental rheumatoid arthritis (RA) rats as observed in our previous studies, while suppression of LXRα by silybin ameliorates arthritis and abnormal lipid metabolism. However, the role of LXRs in RA remains undefined. In this study, we investigated the inhibition role of LXRs in the polarization and activation of M1 macrophage by using a special LXRs inverse agonist SR9243, which led to ameliorating the progression of adjuvant-induced arthritis (AIA) in rats. Mechanistically, SR9243 disrupted the LPS/IFN-γ-induced Warburg effect in M1 macrophages, while glycolysis inhibitor 2-DG attenuated the inhibition effect of SR9243 on M1 polarization and the cytokines expression of M1 macrophages including iNOS, TNF-α, and IL-6 in vitro. Furthermore, SR9243 downregulated key glycolytic enzymes, including LDH-A, HK2, G6PD, GLUT1, and HIF-1α in M1 macrophages, which is mediated by increased phosphorylation of AMPK (Thr172) and reduced downstream phosphorylation of mTOR (Ser2448). Importantly, gene silencing of LXRs compromises the inhibition effect of SR9243 on M1 macrophage polarization and activation. Collectively, for the first time, our findings suggest that the LXR inverse agonist SR9243 mitigates adjuvant-induced rheumatoid arthritis and protects against bone erosion by inhibiting M1 macrophage polarization and activation through modulation of glycolytic metabolism via the AMPK/mTOR/HIF-1α pathway.

Keywords:  experimental rheumatoid arthritis; glycolytic metabolism; inverse agonist SR9243; liver X receptor; macrophage

DOI:  https://doi.org/10.1038/s41401-024-01315-7
mBio. 2024 Jul 10. e0035324

Physiologic medium renders human iPSC-derived macrophages permissive for M. tuberculosis by rewiring organelle function and metabolism.

Claudio Bussi, Rachel Lai, Natalia Athanasiadi, Maximiliano G Gutierrez.

  In vitro studies are crucial for our understanding of the human macrophage immune functions. However, traditional in vitro culture media poorly reflect the metabolic composition of blood, potentially affecting the outcomes of these studies. Here, we analyzed the impact of a physiological medium on human induced pluripotent stem cell (iPSC)-derived macrophages (iPSDM) function. Macrophages cultured in a human plasma-like medium (HPLM) were more permissive to Mycobacterium tuberculosis (Mtb) replication and showed decreased lipid metabolism with increased metabolic polarization. Functionally, we discovered that HPLM-differentiated macrophages showed different metabolic organelle content and activity. Specifically, HPLM-differentiated macrophages displayed reduced lipid droplet and peroxisome content, increased lysosomal proteolytic activity, and increased mitochondrial activity and dynamics. Inhibiting or inducing lipid droplet formation revealed that lipid droplet content is a key factor influencing macrophage permissiveness to Mtb. These findings underscore the importance of using physiologically relevant media in vitro for accurately studying human macrophage function.
IMPORTANCE: This work compellingly demonstrates that the choice of culture medium significantly influences M. tuberculosis replication outcomes, thus emphasizing the importance of employing physiologically relevant media for accurate in vitro host-pathogen interaction studies. We anticipate that our work will set a precedent for future research with clinical relevance, particularly in evaluating antibiotic efficacy and resistance in cellulo.

Keywords:  Mycobacterium tuberculosis; RNA-Seq; lipid droplets; lysosomes; macrophages; metabolism; mitochondria; organelle; physiologic media

DOI:  https://doi.org/10.1128/mbio.00353-24
Cancer Immunol Res. 2024 Jul 08.

MerTK Induces Dysfunctional Dendritic Cells by Metabolic Reprogramming.

Eden Y Zewdie, George M Edwards, Debra M Hunter, H Shelton Earp, Alisha Holtzhausen.

Checkpoint inhibitors, specifically anti-PD-1, have shown success in treating metastatic melanoma; however, some patients develop resistance. Dendritic cells (DCs) play a key role in initiating an immune response but in certain circumstances they become ineffective. We investigated the role of MerTK, a receptor tyrosine kinase responsible for myeloid cell clearance of dead cells, in the regulation of DC function and metabolism in the tumor microenvironment. Tumors resistant to anti-PD-1 exhibited increased levels of MerTK+ DCs. Treating wild-type DCs with apoptotic dead melanoma cells in vitro resulted in increased MerTK expression, elevated mitochondrial respiration and fatty acid oxidation, and reduced T-cell stimulatory capacity, all characteristics of dysfunctional DCs. In contrast, dead cells had only limited effect on the metabolism of MerTK-deficient DCs, which instead maintained an antigen presenting, stimulatory phenotype. The efficacy of anti-PD-1 to slow tumor progression and induce specific T-cell infiltration was markedly increased in mice with selective ablation of MerTK in the DC compartment, suggesting the possibility of therapeutically targeting MerTK to modulate DC metabolism and function and enhance anti-PD-1 therapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0666
Neural Regen Res. 2025 Apr 01. 20(4): 1178-1191

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming.

Wanxian Luo, Chuanhui Xu, Linxi Li, Yunxiang Ji, Yezhong Wang, Yingjia Li, Yongyi Ye.

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson's disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson's disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography-tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01299
Ann Rheum Dis. 2024 Jul 10. pii: ard-2023-224898. [Epub ahead of print]

Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis.

Markus Kieler, Leona Sophia Prammer, Gerwin Heller, Melanie Hofmann, Simon Sperger, Dominik Hanetseder, Birgit Niederreiter, Andrea Komljenovic, Kristaps Klavins, Thomas Köcher, Julia Stefanie Brunner, Irena Stanic, Laura Oberbichler, Ana Korosec, Andrea Vogel, Martina Kerndl, Dominika Hromadová, Laszlo Musiejovsky, Alexander Hajto, Anja Dobrijevic, Tina Piwonka, Arvand Haschemi, Anne Miller, Philippe Georgel, Darja Marolt Presen, Johannes Grillari, Silvia Hayer, Jean-Philippe Auger, Gerhard Krönke, Omar Sharif, Daniel Aletaha, Gernot Schabbauer, Stephan Blüml.

   OBJECTIVES: Bone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis.
METHODS: We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterised by quantitative PCR and western blot. Osteoblast function was assessed by Alizarin red staining. immunoresponsive gene 1 (Irg1)-deficient mice were used in various inflammatory or non-inflammatory models of bone loss. Tissue gene expression was analysed by RNA in situ hybridisation.
RESULTS: We show that during differentiation preosteoclasts rearrange their tricarboxylic acid cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterised by the induction of Irg1 and production of itaconate, which accumulates intracellularly and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generation in vitro and in vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation in both human and murine cells. This enhanced osteogenic differentiation is accompanied by reduced proliferation and altered metabolism. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely, Irg1-deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis.
CONCLUSION: In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognised regulator of osteoblasts.

Keywords:  arthritis, experimental; bone density; spondylitis, ankylosing

DOI:  https://doi.org/10.1136/ard-2023-224898
Gut. 2024 Jul 09. pii: gutjnl-2024-332429. [Epub ahead of print]

Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.

Yang Yang, Tianduo Pei, Chaobao Liu, Mingtao Cao, Xiaolin Hu, Jie Yuan, Fengqian Chen, Bao Guo, Yuemei Hong, Jibin Liu, Bin Li, Xiaoguang Li, Hui Wang.

   OBJECTIVE: The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.
DESIGN: Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells.
RESULTS: We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression.
CONCLUSION: Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.

Keywords:  HEPATOCELLULAR CARCINOMA; IMMUNOLOGY IN HEPATOLOGY; IMMUNOTHERAPY

DOI:  https://doi.org/10.1136/gutjnl-2024-332429
mBio. 2024 Jul 12. e0121124

Seeing the unseen: illuminating Toxoplasma gondii's metabolic manipulation.

Diego Huet, Victoria Jeffers.

  Intracellular infection by a pathogen induces significant rewiring of host cell signaling and biological processes. Understanding how an intracellular pathogen such as Toxoplasma gondii modulates host cell metabolism with single-cell resolution has been challenged by the variability of infection within cultures and difficulties in separating host and parasite metabolic processes. A new study from Gallego-Lopez and colleagues (G. M. Gallego-López, E. C. Guzman, D. E. Desa, L. J. Knoll, M. C. Skala, mBio e00727-24, 2024, https://doi.org/10.1128/mbio.00727-24) applies a quantitative imaging approach to evaluate the host cell metabolism during intracellular infection with Toxoplasma. This study provides important insights into host metabolic responses to Toxoplasma infection and offers a valuable tool to dissect the mechanisms underlying parasite infection and pathophysiology.

Keywords:  apicomplexan parasites; confocal microscopy; host-pathogen interactions; metabolism

DOI:  https://doi.org/10.1128/mbio.01211-24
bioRxiv. 2024 Jun 28. pii: 2024.06.24.600383. [Epub ahead of print]

Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.

Samarth Hegde, Bruno Giotti, Brian Y Soong, Laszlo Halasz, Jessica Le Berichel, Assaf Magen, Benoit Kloeckner, Raphaël Mattiuz, Matthew D Park, Adam Marks, Meriem Belabed, Pauline Hamon, Theodore Chin, Leanna Troncoso, Juliana J Lee, Dughan Ahimovic, Michael Bale, Grace Chung, Darwin D'souza, Krista Angeliadis, Travis Dawson, Seunghee Kim-Schulze, Raja M Flores, Andrew J Kaufman, Florent Ginhoux, Steven Z Josefowicz, Sai Ma, Alexander M Tsankov, Thomas U Marron, Brian D Brown, Miriam Merad.

Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.

DOI: https://doi.org/10.1101/2024.06.24.600383
J Nutr Biochem. 2024 Jul 05. pii: S0955-2863(24)00132-3. [Epub ahead of print] 109699

Dietary pectin and inulin: a promising adjuvant supplement for collagen-induced arthritis through gut microbiome restoration and CD4+ T cell reconstitution.

Yu Lou, Xianghui Wen, Siyue Song, Yufeng Zeng, Lin Huang, Zhijun Xie, Tiejuan Shao, Chengping Wen.

  Dietary strategies rich in fiber have been demonstrated to offer benefits to individuals afflicted with rheumatoid arthritis (RA). However, the specific mechanisms through which a high-fiber diet (HFD) mitigates RA's autoimmunity remain elusive. Herein, we investigate the influence of pectin- and inulin-rich HFD on collagen-induced arthritis (CIA). We establish that HFD significantly alleviates arthritis in CIA mice by regulating the Th17/Treg balance. The rectification of aberrant T cell differentiation by the HFD is linked to the modulation of gut microbiota, augmenting the abundance of butyrate in feces. Concurrently, adding butyrate to the drinking water mirrors the HFD's impact on ameliorating CIA, encompassing arthritis mitigation, regulating intestinal barrier integrity, and restoring the Th17/Treg equilibrium. Butyrate reshapes the metabolic profile of CD4+ T cells in an AMPK-dependent manner. Our research underscores the importance of dietary interventions in rectifying gut microbiota for RA management and offers an explanation of how diet-derived microbial metabolites influence RA's immune-inflammatory-reaction.

Keywords:  AMPK; Butyrate; CD4(+) T cells; Glycolysis; High fiber diet; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109699
Nat Commun. 2024 Jul 12. 15(1): 5851

Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer.

Xiaojun Zhou, Genxin Wang, Chenhui Tian, Lin Du, Edward V Prochownik, Youjun Li.

Tumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion. Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME). There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC.

DOI: https://doi.org/10.1038/s41467-024-50138-x
J Immunol Res. 2024 ;2024 2506586

12,13-diHOME Promotes Inflammatory Macrophages and Epigenetically Modifies Their Capacity to Respond to Microbes and Allergens.

Din L Lin, Kevin M Magnaye, Cara E Porsche, Sophia R Levan, Elze Rackaityte, Mustafa Özçam, Susan V Lynch.

Elevated infant fecal concentrations of the bacterial-derived lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) increase the risk for childhood atopy and asthma. However, the mechanisms by which this lipid contributes to disease development are largely unknown. We hypothesized that macrophages, which are key to both antimicrobial and antigen responses, are functionally and epigenetically modified by 12,13-diHOME leading to short- and long-term dysfunction with consequences for both antimicrobial and antigenic responses. Macrophages exposed to 12,13-diHOME are skewed toward inflammatory IL-1β highCD206low cells, a phenomenon that is further amplified in the presence of common microbial-, aero-, and food-allergens. These IL-1β highCD206low macrophages also exhibit reduced bacterial phagocytic capacity. In primary immune cell coculture assays involving peanut allergen stimulation, 12,13-diHOME promotes both IL-1β and IL-6 production, memory B cell expansion, and increased IgE production. Exposure to 12,13-diHOME also induces macrophage chromatin remodeling, specifically diminishing access to interferon-stimulated response elements resulting in reduced interferon-regulated gene expression upon bacterial lipopolysaccharide stimulation. Thus 12,13-diHOME reprograms macrophage effector function, B-cell interactions and promotes epigenetic modifications that exacerbate inflammatory response to allergens and mutes antimicrobial response along the interferon axis. These observations offer plausible mechanisms by which this lipid promotes early-life pathogenic microbiome development and innate immune dysfunction associated with childhood allergic sensitization.

DOI: https://doi.org/10.1155/2024/2506586
Trends Endocrinol Metab. 2024 Jul;pii: S1043-2760(24)00086-9. [Epub ahead of print]35(7): 561-562

Aconitate decarboxylase (ACOD1) has found a disease.

Fakhar H Waqas, Chutao Chen, Frank Pessler.



Keywords:  ACOD1; IRG1; cancer; citraconic acid; immune checkpoint inhibitors; immuno-oncology; itaconic acid; metabolism; tricarboxylic acid cycle; tumor microenvironment

DOI:  https://doi.org/10.1016/j.tem.2024.04.003
Cell Death Dis. 2024 Jul 09. 15(7): 491

IL-27 disturbs lipid metabolism and restrains mitochondrial activity to inhibit γδ T17 cell-mediated skin inflammation.

Mingyue Zhang, Dehai Li, Jing Zhu, Xue Xia, Hua Zhang, Jie Wu, Shengli Wang, Anyi Deng, Qiong Wen, Jingyi Tan, Jianlei Hao, Jun Jiang, Xiucong Bao, Guodong Sun, Jiajing Lu, Quanli Yang, Hengwen Yang, Guangchao Cao, Zhinan Yin, Qian Wang.

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.

DOI: https://doi.org/10.1038/s41419-024-06887-0
mSphere. 2024 Jul 09. e0036924

Selective host autophagy is induced during the intracellular parasite Toxoplasma gondii infection controlling amino acid levels.

Matthew D White, Rajendra K Angara, Leticia Torres Dias, Dhananjay D Shinde, Vinai C Thomas, Leonardo Augusto.

  Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistant to available drugs. For its chronic persistence in the brain, the parasite relies on host cells' nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustain its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in the accumulation of unfolded protein within the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.
IMPORTANCE: Intracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host. Toxoplasma gondii, a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals that T. gondii induces the host's autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasite's chronic forms. Significantly, our investigation establishes the crucial role of host endoplasmic reticulum (ER)-phagy in the parasite's persistence within the host during latent infection.

Keywords:  ER-phagy; Toxoplasma gondii; amino acid; behavior; endoplasmic reticulum

DOI:  https://doi.org/10.1128/msphere.00369-24
Cell Rep. 2024 Jul 10. pii: S2211-1247(24)00819-2. [Epub ahead of print]43(7): 114490

Sugar and arginine facilitate oral tolerance by ensuring the functionality of tolerogenic immune cell subsets in the intestine.

Motoyoshi Nagai, Takuma Okawa, Kazuaki Nakata, Daisuke Takahashi, Reina Miyajima, Hiroaki Shiratori, Daisuke Yamanaka, Atsuo Nakamura, Chinatsu Oyama, Shin-Ichiro Takahashi, Noriko Toyama-Sorimachi, Koichiro Suzuki, Wakana Ohashi, Taeko Dohi, Yuki I Kawamura, Koji Hase.

  Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.

Keywords:  CP: Immunology; CP: Metabolism; CX3CR1(+) cells; allergy; dendritic cells; fasting; food antigens; mTOR signaling; metabolic rewiring; nutrition; oral tolerance; regulatory T cells

DOI:  https://doi.org/10.1016/j.celrep.2024.114490
Mol Metab. 2024 Jul 04. pii: S2212-8778(24)00112-1. [Epub ahead of print] 101981

Metabolic profiling of single cells by exploiting NADH and FAD fluorescence via flow cytometry.

Ariful Haque Abir, Leonie Weckwerth, Artur Wilhelm, Jana Thomas, Clara M Reichardt, Luis Munoz, Simon Völkl, Uwe Appelt, Markus Mroz, Raluca Niesner, Anja Hauser, Rebecca Sophie Fischer, Katharina Pracht, Hans-Martin Jäck, Georg Schett, Gerhard Krönke, Dirk Mielenz.

  The metabolism of different cells within the same microenvironment can differ and dictate physiological or pathological adaptions. Current single-cell analysis methods of metabolism are not label-free. The study introduces a label-free, live-cell analysis method assessing endogenous fluorescence of NAD(P)H and FAD in surface-stained cells by flow cytometry. OxPhos inhibition, mitochondrial uncoupling, glucose exposure, genetic inactivation of glucose uptake and mitochondrial respiration alter the optical redox ratios of FAD and NAD(P)H as measured by flow cytometry. Those alterations correlate strongly with measurements obtained by extracellular flux analysis. Consequently, metabolically distinct live B-cell populations can be resolved, showing that human memory B-cells from peripheral blood exhibit a higher glycolytic flexibility than naïve B cells. Moreover, the comparison of blood-derived B- and T-lymphocytes from healthy donors and rheumatoid arthritis patients unleashes rheumatoid arthritis-associated metabolic traits in human naïve and memory B-lymphocytes. Taken together, these data show that the optical redox ratio can depict metabolic differences in distinct cell populations by flow cytometry.

Keywords:  FAD; Flow cytometry; Fluorescence; Metabolism; NADH; Real-time

DOI:  https://doi.org/10.1016/j.molmet.2024.101981
Cytokine Growth Factor Rev. 2024 Jul 06. pii: S1359-6101(24)00045-5. [Epub ahead of print]

The anti-inflammatory effects of itaconate and its derivatives in neurological disorders.

Xiangyi Kong, Lin Xu, Zheng Mou, Wenyuan Lyu, Kaiyue Shan, Longfei Wang, Fanghao Liu, Fei Rong, Jianjun Li, Penghui Wei.

  Almost 16 % of the global population is affected by neurological disorders, including neurodegenerative and cerebral neuroimmune diseases, triggered by acute or chronic inflammation. Neuroinflammation is recognized as a common pathogenic mechanism in a wide array of neurological conditions including Alzheimer's disease, Parkinson's disease, postoperative cognitive dysfunction, stroke, traumatic brain injury, and multiple sclerosis. Inflammatory process in the central nervous system (CNS) can lead to neuronal damage and neuronal apoptosis, consequently exacerbating these diseases. Itaconate, an immunomodulatory metabolite from the tricarboxylic acid cycle, suppresses neuroinflammation and modulates the CNS immune response. Emerging human studies suggest that itaconate levels in plasma and cerebrospinal fluid may serve as biomarkers associated with inflammatory responses in neurological disorders. Preclinical studies have shown that itaconate and its highly cell-permeable derivatives are promising candidates for preventing and treating neuroinflammation-related neurological disorders. The underlying mechanism may involve the regulation of immune cells in the CNS and neuroinflammation-related signaling pathways and molecules including Nrf2/KEAP1 signaling pathway, reactive oxygen species, and NLRP3 inflammasome. Here, we introduce the metabolism and function of itaconate and the synthesis and development of its derivatives. We summarize the potential impact and therapeutic potential of itaconate and its derivatives on brain immune cells and the associated signaling pathways and molecules, based on preclinical evidence via various neurological disorder models. We also discuss the challenges and potential solutions for clinical translation to promote further research on itaconate and its derivatives for neuroinflammation-related neurological disorders.

Keywords:  Itaconate; NLRP3 inflammasome; Neuroinflammation; Neurological disorders; Nrf2/KEAP1 signaling pathway; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cytogfr.2024.07.001
Nat Microbiol. 2024 Jul 12.

Bacterial reprogramming of tick metabolism impacts vector fitness and susceptibility to infection.

Sourabh Samaddar, Agustin Rolandelli, Anya J O'Neal, Hanna J Laukaitis-Yousey, Liron Marnin, Nisha Singh, Xiaowei Wang, L Rainer Butler, Parisa Rangghran, Chrysoula Kitsou, Francy E Cabrera Paz, Luisa Valencia, Camila R Ferraz, Ulrike G Munderloh, Benedict Khoo, Benjamin Cull, Kristin L Rosche, Dana K Shaw, Jonathan Oliver, Sukanya Narasimhan, Erol Fikrig, Utpal Pal, Gary M Fiskum, Brian M Polster, Joao H F Pedra.

Arthropod-borne pathogens are responsible for hundreds of millions of infections in humans each year. The blacklegged tick, Ixodes scapularis, is the predominant arthropod vector in the United States and is responsible for transmitting several human pathogens, including the Lyme disease spirochete Borrelia burgdorferi and the obligate intracellular rickettsial bacterium Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis. However, tick metabolic response to microbes and whether metabolite allocation occurs upon infection remain unknown. Here we investigated metabolic reprogramming in the tick ectoparasite I. scapularis and determined that the rickettsial bacterium A. phagocytophilum and the spirochete B. burgdorferi induced glycolysis in tick cells. Surprisingly, the endosymbiont Rickettsia buchneri had a minimal effect on bioenergetics. An unbiased metabolomics approach following A. phagocytophilum infection of tick cells showed alterations in carbohydrate, lipid, nucleotide and protein metabolism, including elevated levels of the pleiotropic metabolite β-aminoisobutyric acid. We manipulated the expression of genes associated with β-aminoisobutyric acid metabolism in I. scapularis, resulting in feeding impairment, diminished survival and reduced bacterial acquisition post haematophagy. Collectively, we discovered that metabolic reprogramming affects interspecies relationships and fitness in the clinically relevant tick I. scapularis.

DOI: https://doi.org/10.1038/s41564-024-01756-0
Mol Metab. 2024 Jul 09. pii: S2212-8778(24)00117-0. [Epub ahead of print] 101986

Alpha-melanocyte-stimulating hormone contributes to an anti-inflammatory response to lipopolysaccharide in male C57BL6/J mice.

R P Reynolds, R R Fan, A Tinajero, X Luo, S C Huen, T Fujikawa, S Lee, A Lemoff, K G Mountjoy, J K Elmquist.

   OBJECTIVE: During infection, metabolism and immunity react dynamically to promote survival through mechanisms that remain unclear. Pro-opiomelanocortin (POMC) cleavage products are produced and released in the brain and in the pituitary gland. One POMC cleavage product, alpha-melanocyte-stimulating hormone (α-MSH), is known to regulate food intake and energy expenditure and has anti-inflammatory effects. However, it is not known whether α-MSH is required to regulate physiological anti-inflammatory responses. We recently developed a novel mouse model with a targeted mutation in Pomc (Pomctm1/tm1 mice) to block production of all α-MSH forms which are required to regulate metabolism. To test whether endogenous α-MSH is required to regulate immune responses, we compared acute bacterial lipopolysaccharide (LPS)-induced inflammation between Pomctm1/tm1 and wild-type Pomcwt/wt mice.
METHODS: We challenged 10 to 14-week-old male Pomctm1/tm1 and Pomcwt/wt mice with single i.p. injections of either saline or low-dose LPS (100 μg/kg) and monitored immune and metabolic responses. We used telemetry to measure core body temperature (Tb), ELISA to measure circulating cytokines, corticosterone and α-MSH, and metabolic chambers to measure body weight, food intake, activity, and respiration. We also developed a mass spectrometry method to measure three forms of α-MSH produced in the mouse hypothalamus and pituitary gland.
RESULTS: LPS induced an exaggerated immune response in Pomctm1/tm1 compared to Pomcwt/wt mice. Both groups of mice were hypoactive and hypothermic following LPS administration, but Pomctm1/tm1 mice were significantly more hypothermic compared to control mice injected with LPS. Pomctm1/tm1 mice also had reduced oxygen consumption and impaired metabolic responses to LPS compared to controls. Pomctm1/tm1 mice had increased levels of key proinflammatory cytokines at 2 h and 4 h post LPS injection compared to Pomcwt/wt mice. Lastly, Pomcwt/wt mice injected with LPS compared to saline had increased total α-MSH in circulation 2 h post injection.
CONCLUSION: Our data indicate endogenous α-MSH contributes to the inflammatory immune responses triggered by low-dose LPS administration and suggest that targeting the melanocortin system could be a potential therapeutic for the treatment of sepsis or inflammatory disease.

Keywords:  LPS; POMC; mouse model; thermogenesis; α-MSH

DOI:  https://doi.org/10.1016/j.molmet.2024.101986
Sci Rep. 2024 Jul 10. 14(1): 15993

Immune cells phenotype and bioenergetic measures in CD4+ T cells differ between high and low feed efficient dairy cows.

Usman Arshad, Katherine M Kennedy, Malena Cid de la Paz, Sophia J Kendall, Lautaro R Cangiano, Heather M White.

Identifying sources of variance that contribute to residual feed intake (RFI) can aid in improving feed efficiency. The objectives of this study were to investigate immune cells phenotype and bioenergetic measures in CD4+ T cells in low feed efficient (LE) and high feed efficient (HE) dairy cows. Sixty-four Holstein cows were enrolled at 93 ± 22 days in milk (DIM) and monitored for 7 weeks to measure RFI. Cows with the highest RFI (LE; n = 14) or lowest RFI (HE; n = 14) were selected to determine immune cells phenotype using flow cytometry. Blood was sampled in the same LE and HE cows at 234 ± 22 DIM to isolate peripheral blood mononuclear cells, followed by magnetic separation of CD4+ T lymphocytes using bovine specific monoclonal antibodies. The metabolic function of isolated CD4+ T lymphocytes was evaluated under resting and activated states. An increased expression of CD62L+ cells within CD8+ T lymphocytes and CD21+ B lymphocytes was observed in HE cows compared to LE cows. CD4+ T lymphocytes of HE cows exhibited an increased mitochondrial and glycolytic activity in resting and activated states compared to LE cows. These data suggest that immune cells in HE cows exhibit an increased metabolic function, which might influence nutrient partitioning and utilization and serve as a source of variation in feed efficiency that warrants future investigation.

DOI: https://doi.org/10.1038/s41598-024-66345-x
J Nutr. 2024 Jul 05. pii: S0022-3166(24)00381-X. [Epub ahead of print]

Metformin as a therapeutic agent for obesity-associated immune dysfunction.

Devika Rajeev, Nancie J MacIver.

  Obesity is associated with impaired immune function, characterized by inflammation, and leading to poor response to infection, impaired vaccine response, increased susceptibility to autoimmune disease, and increased risk of cancer and cancer mortality. Worse, there is evidence that weight loss alone may be insufficient to reverse the immune dysfunction caused by obesity. It is therefore critically important to identify alternative therapeutic approaches to decrease the negative effects of obesity-associated inflammation. Here, we will review evidence that the antidiabetic drug metformin may be considered as a therapeutic agent for obesity-associated immune dysfunction. Metformin has immune-modulatory effects, stimulating or suppressing the immune response in both a cell-specific and disease-specific manner. Although the mechanism of action of metformin on the immune system remains to be fully elucidated, there is strong evidence that metformin enters select immune cells and disrupts electron transport, leading to both AMPK-dependent and AMPK-independent effects on immune cell differentiation and cytokine production. These effects of metformin on immune cells have been shown to improve immune responses to infection, autoimmunity, and cancer.

Keywords:  Metformin; autoimmunity; immunity; obesity; tumor immunity; viral infection

DOI:  https://doi.org/10.1016/j.tjnut.2024.07.001
Nat Commun. 2024 Jul 06. 15(1): 5680

ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells.

Tu-Xiong Huang, Hui-Si Huang, Shao-Wei Dong, Jia-Yan Chen, Bin Zhang, Hua-Hui Li, Tian-Tian Zhang, Qiang Xie, Qiao-Yun Long, Yang Yang, Lin-Yuan Huang, Pan Zhao, Jiong Bi, Xi-Feng Lu, Fan Pan, Chang Zou, Li Fu.

Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-β1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-β1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

DOI: https://doi.org/10.1038/s41467-024-50077-7
Mucosal Immunol. 2024 Jul 09. pii: S1933-0219(24)00067-9. [Epub ahead of print]

Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway.

Chen-Ting Hung, Changqing Ma, Santosh K Panda, Tihana Trsan, Miki Hodel, Jennifer Frein, Amanda Foster, Shengxiang Sun, Hung-Ting Wu, Justin Kern, Richa Mishra, Umang Jain, Ya-Chi Ho, Marco Colonna, Thaddeus S Stappenbeck, Ta-Chiang Liu.

  The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

Keywords:  adaptive immunity; fatty acid; macrophages; obesity

DOI:  https://doi.org/10.1016/j.mucimm.2024.07.001
Cell Metab. 2024 Jun 28. pii: S1550-4131(24)00233-X. [Epub ahead of print]

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.

Mengqi Zheng, Yunjiao Zhai, Yanbo Yu, Jing Shen, Shuzheng Chu, Enrico Focaccia, Wenyu Tian, Sui Wang, Xuesong Liu, Xi Yuan, Yue Wang, Lixiang Li, Bingcheng Feng, Zhen Li, Xiaohuan Guo, Ju Qiu, Cuijuan Zhang, Jiajie Hou, Yiyuan Sun, Xiaoyun Yang, Xiuli Zuo, Mathias Heikenwalder, Yanqing Li, Detian Yuan, Shiyang Li.

  The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Keywords:  bile acid; detoxification; infliximab; tumor necrosis factor; ulcerative colitis

DOI:  https://doi.org/10.1016/j.cmet.2024.06.008
Anal Biochem. 2024 Jul 10. pii: S0003-2697(24)00149-0. [Epub ahead of print]694 115605

Derivative spectrophotometry-assisted determination of tryptophan metabolites emerges host and intestinal flora dysregulations during sepsis.

Mengyu Jiang, Li Li, Yuan Jin, Liuliu Lu, Zhenchen Lu, Wangjie Lv, Xiaoqun Wang, Lei Di, Zhicheng Liu.

  Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. Dysregulated tryptophan (TRP) metabolites serve as significant indicators for endogenous immune turnovers and abnormal metabolism in the intestinal microbiota during sepsis. Therefore, a high coverage determination of TRP and its metabolites in sepsis is beneficial for the diagnosis and prognosis of sepsis, as well as for understanding the underlying mechanism of sepsis development. However, similar structures in TRP metabolites make it challenging for separation and metabolite identification. Here, high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD) was developed to determine TRP metabolites in rat serum. The first-order derivative spectrophotometry of targeted metabolites in the serum was investigated and proved to be promising for chromatographic peak annotation across different columns and systems. The established method separating the targeted metabolites was optimized and validated to be sensitive and accurate. Application of the method revealed dysregulated TRP metabolites, associated with immune disorders and NAD + metabolism in both the host and gut flora in septic rats. Our findings indicate that the derivative spectrophotometry-assisted method enhances metabolite identifications for the chromatographic systems based on DAD detectors and holds promise for precision medicine in sepsis.

Keywords:  Biomarkers; Derivative spectrophotometry; HPLC-DAD; Sepsis; Tryptophan metabolites

DOI:  https://doi.org/10.1016/j.ab.2024.115605
Immunol Rev. 2024 Jul 11.

Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.

Daniel C Shippy, Abigail H Evered, Tyler K Ulland.

  Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.

Keywords:  Alzheimer's disease; Beta‐hydroxybutyrate; NLRP3 inflammasome; ketone bodies; metabolism; microglia

DOI:  https://doi.org/10.1111/imr.13365
J Immunother Cancer. 2024 Jul 08. pii: e008811. [Epub ahead of print]12(7):

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.

Yang Chen, Yu Zhou, Ran Ren, Yu Chen, Juan Lei, Yongsheng Li.

   BACKGROUND: While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.
METHODS: Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.
RESULTS: We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.
CONCLUSIONS: These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.

Keywords:  Immune Checkpoint Inhibitor; Lung Cancer; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-008811
J Acquir Immune Defic Syndr. 2024 Aug 15. 96(5): 494-500

Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV.

Eran Frank Shorer, Raha M Dastgheyb, Audrey L French, Elizabeth Daubert, Ralph Morack, Tsion Yohannes, Clary Clish, Deborah Gustafson, Anjali Sharma, Andre Rogando, Qibin Qi, Helen Burgess, Leah H Rubin, Kathleen M Weber.

BACKGROUND: Immune and cognitive dysfunction persists even in virally suppressed women with HIV (VS-WWH). Since inflammation and HIV proteins induce the enzyme indoleamine 2,3-dioxygenase (IDO), converting tryptophan (T) to kynurenine (K) while producing downstream neurotoxic metabolites, we investigated IDO activation (KT ratio) in relation to cognition in VS-WWH and demographically similar women without HIV (WWoH).
METHODS: Ninety-nine VS-WWH on stable antiretroviral therapy and 102 WWoH (median age 52 vs 54 years; 73% vs 74% Black, respectively) from the New York and Chicago sites of the Women's Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function and had plasma measured for tryptophan-kynurenine metabolites through liquid chromatography-tandem mass spectrometry and monocyte-derived [soluble cluster of differentiation-14 (sCD14), soluble cluster of differentiation-163 (sCD163), monocyte chemoattractant protein-1 (MCP-1)] plus general inflammatory markers [tumor necrosis factor alpha-2 receptor (TNF-R2), high-sensitivity C-reactive protein, high-sensitivity interleukin-6] through enzyme-linked immunosorbent assays between 2017 and 2020.
RESULTS: VS-WWH had a higher KT ratio (P < 0.01) and higher sCD14 levels (P < 0.05) compared with WWoH. Higher sCD163 was associated with higher KT ratio (R = 0.29, P < 0.01) and worse fine motor function in VS-WWH; after adjusting for sCD163 and sCD14 in multivariable regressions, higher KT ratio remained significantly associated with impaired fine motor function in VS-WWH only (standardized β = -0.29, P < 0.05). IDO activation was not associated with cognition in WWoH.
CONCLUSIONS: IDO activation (K:T) was associated with worse fine motor control in VS-WWH independent of measured systemic inflammation. Further studies investigating biological mechanisms linking IDO activation to fine motor function among VS-WWH are warranted.

DOI: https://doi.org/10.1097/QAI.0000000000003454
Eur J Immunol. 2024 Jul 07. e2350655

α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Gang Liang, Jia-Yan Hu, Rou-Jun Liu, Yu-Peng Chao, Yi-Fan Hu, Hong Zheng, Xin-Yu Pan, Yuan-Jing Li, Yang-Hui Gong, Chi Lin, Jia-Hao Lin, Jia-Dong Wang, Tong-Xin Li, Jian-Ping Pan, Dong-Yang Guo.

  Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

Keywords:  SR‐A5; Sepsis; m6A methylation; α‐Ketoglutarate

DOI:  https://doi.org/10.1002/eji.202350655
FASEB J. 2024 Jul 31. 38(14): e23807

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Hong Yong Peh, Robert Nshimiyimana, Thayse R Brüggemann, Melody G Duvall, Julie Nijmeh, Charles N Serhan, Bruce D Levy.

  Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

Keywords:  15‐HEPE; air pouch; efferocytosis; resolution of inflammation; specialized proresolving mediators

DOI:  https://doi.org/10.1096/fj.202400610R
Int Immunopharmacol. 2024 Jul 09. pii: S1567-5769(24)01153-6. [Epub ahead of print]138 112632

Kidney targeting and modulating macrophage polarization through AMPK signaling: Therapeutic mechanism of berberine in uric acid nephropathy.

Shiting Gong, Jingzhi Chen, Xiaohong Zheng, Xiaowei Lu, Manru Chen, Jincan Li, Ziren Su, Yuhong Liu, Jiannan Chen, Jianhui Xie, Qingfeng Xie, Yucui Li.

  Uric acid nephropathy (UAN), caused by a common metabolic disorder resulting from hyperuricemia (HUA), has an increasing incidence. Previous studies have shown that berberine (BBR) has clear urate-lowering and anti-inflammatory effects in UAN mice, but its mechanism needs to be further clarified. Therefore, Potassium Oxonate (PO) combined with hypoxanthine (HX) induced UAN mice model and MSU induced THP-1 cells polarization model were adopted to investigate the mechanism of BBR on UAN in terms of tissue distribution and molecular pharmacology. Study unveiled that BBR was first found to bind to red blood cells (RBCs), which were recognized and phagocytosed by monocytes, then recruited by the injured kidney. Subsequently, BBR was enriched and functional in damaged kidney. The results of in vivo experiments revealed that, BBR reduced UA, BUN, CRE levels as well as the release of TNF-α, IL-1β, IL-18 and IL-6, and alleviated renal injury in UAN mice, as consistent with previous studies. Additionally, BBR decreased MCP-1 expression, while diminishing macrophage infiltration and decreasing M1 proportion as determined by RT-qPCR. In vitro experiments, demonstrated that MSU promoted inflammatory polarization of THP-1 cells, while BBR reduced synthesis of inflammatory factors and inhibited MSU-induced inflammatory polarization. These effects of BBR were dependent on AMPK activation along with indirect inhibition of NF-κB signaling pathway mediated. However, the anti-inflammatory and macrophage polarization regulation effects of BBR were completely reversed upon administration of Compound C, an AMPK inhibitor. Therefore, BBR ameliorated kidney injury via regulating macrophage polarization through AMPK, which has therapeutic potential for UAN patients.

Keywords:  AMPK; Berberine; Kidney targeting; Macrophages; Uric acid nephropathy

DOI:  https://doi.org/10.1016/j.intimp.2024.112632