bims-imicid 2024-02-04 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–02–04
23 papers selected by
Dylan Ryan, University of Cambridge

Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.
Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.
Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
Sulforaphane impedes mitochondrial reprogramming and histone acetylation in polarizing M1 (LPS) macrophages.
Virus-induced host cell metabolic alteration.
Angiotensin-(1-7) Modulates the Warburg Effect to Alleviate Inflammation in LPS-Induced Macrophages and Septic Mice.
IKAROS expression drives the aberrant metabolic phenotype of macrophages in chronic HIV infection.
Metabolomic landscape of macrophage discloses an anabolic signature of dengue virus infection and antibody-dependent enhancement of viral infection.
The intersection of host in vivo metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites.
Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.
ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.
Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism.
Metabolic reprogramming in the tumor microenvironment of liver cancer.
The emerging role for neutrophil mitochondrial metabolism in lung inflammation.
Composition of fatty acids in a high-fat diet affects adipose tissue inflammation by inducing calreticulin on adipocytes and activating group 1 innate lymphoid cells.
Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.
Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.
p53 promotes antiviral innate immunity by driving hexosamine metabolism.
Exogenous butyrate inhibits butyrogenic metabolism and alters virulence phenotypes in Clostridioides difficile.
MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.
Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase.
RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Nat Cancer. 2024 Jan 29.

Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.

Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

DOI: https://doi.org/10.1038/s43018-023-00721-w
Elife. 2024 Feb 02. pii: RP92420. [Epub ahead of print]12

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation.

Rabina Mainali, Nancy Buechler, Cristian Otero, Laken Edwards, Chia-Chi Key, Cristina Furdui, Matthew A Quinn.

  One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Acod1 knockout mice that are deficient in synthesizing itaconate, we aimed to understand the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Acod1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveals enhanced expression of enzymes involved in fatty acid oxidation in following 4-octyl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Acod1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

Keywords:  fatty acid oxidation; immunology; inflammation; itaconate; mouse

DOI:  https://doi.org/10.7554/eLife.92420
Mol Metab. 2024 Jan 31. pii: S2212-8778(24)00019-X. [Epub ahead of print] 101888

Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.

Marissa N Trujillo, Erin Q Jennings, Emely A Hoffman, Hao Zhang, Aiden M Phoebe, Grace E Mastin, Naoya Kitamura, Julie A Reisz, Emily Megill, Daniel Kantner, Mariola M Marcinkiewicz, Shannon M Twardy, Felicidad Lebario, Eli Chapman, Rebecca L McCullough, Angelo D'Alessandro, Nathaniel W Snyder, Darren A Cusanovich, James J Galligan.

  Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.

Keywords:  Metabolism; glyoxalase; inflammation; lactate; post-translational modification

DOI:  https://doi.org/10.1016/j.molmet.2024.101888
FASEB J. 2024 Feb 15. 38(3): e23450

Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?

Chengcheng Peng, Pengpeng Xiao, Nan Li.

  Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.

Keywords:  glucose metabolism; glutamine metabolism; immune microenvironment; lipid metabolism; metabolic reprogramming; oncolytic virus; oxidative phosphorylation

DOI:  https://doi.org/10.1096/fj.202301947RR
Free Radic Biol Med. 2024 Jan 30. pii: S0891-5849(24)00037-6. [Epub ahead of print]

Sulforaphane impedes mitochondrial reprogramming and histone acetylation in polarizing M1 (LPS) macrophages.

Sheyda Bahiraii, Martin Brenner, Wolfram Weckwerth, Elke H Heiss.

  M1 (LPS) macrophages are characterized by a high expression of pro-inflammatory mediators, and distinct metabolic features that comprise increased glycolysis, a broken TCA cycle, or impaired OXPHOS with augmented mitochondrial ROS production. This study investigated whether the phytochemical sulforaphane (Sfn) influences mitochondrial reprogramming during M1 polarization, as well as to what extent this can contribute to Sfn-mediated inhibition of M1 marker expression in murine macrophages. The use of extracellular flux-, metabolite-, and immunoblot analyses as well as fluorescent dyes indicative for mitochondrial morphology, membrane potential or superoxide production, demonstrated that M1 (LPS/Sfn) macrophages maintain an unbroken TCA cycle, higher OXPHOS rate, boosted fusion dynamics, lower membrane potential, and less superoxide production in their mitochondria when compared to control M1 (LPS) cells. Sustained OXPHOS and TCA activity but not the concomitantly observed high dependency on fatty acids as fuel appeared necessary for M1 (LPS/Sfn) macrophages to reduce expression of nos2, il1β, il6 and tnfα. M1 (LPS/Sfn) macrophages also displayed lower nucleo/cytosolic acetyl-CoA levels in association with lower global and site-specific histone acetylation at selected pro-inflammatory gene promoters than M1 (LPS), evident in colorimetric coupled enzyme assays, immunoblot and ChIP-qPCR analyses, respectively. Supplementation with acetate or citrate was able to rescue both histone acetylation and mRNA expression of the investigated M1 marker genes in Sfn-treated cells. Overall, Sfn preserves mitochondrial functionality and restricts indispensable nuclear acetyl-CoA for histone acetylation and M1 marker expression in LPS-stimulated macrophages.

Keywords:  Fatty acid synthesis; Histone acetylation; Immunometabolism; M1 macrophages; Mitochondria; Sulforaphane

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.029
Rev Med Virol. 2024 Jan;34(1): e2505

Virus-induced host cell metabolic alteration.

Syed Shahariar Bappy, Md Muzammal Haque Asim, Mohammad Mainul Ahasan, Asif Ahsan, Sorna Sultana, Roksana Khanam, Abu Zaffar Shibly, Yearul Kabir.

  Viruses change the host cell metabolism to produce infectious particles and create optimal conditions for replication and reproduction. Numerous host cell pathways have been modified to ensure available biomolecules and sufficient energy. Metabolomics studies conducted over the past decade have revealed that eukaryotic viruses alter the metabolism of their host cells on a large scale. Modifying pathways like glycolysis, fatty acid synthesis and glutaminolysis could provide potential energy for virus multiplication. Thus, almost every virus has a unique metabolic signature and a different relationship between the viral life cycle and the individual metabolic processes. There are enormous research in virus induced metabolic reprogramming of host cells that is being conducted through numerous approaches using different vaccine candidates and antiviral drug substances. This review provides an overview of viral interference to different metabolic pathways and improved monitoring in this area will open up new ways for more effective antiviral therapies and combating virus induced oncogenesis.

Keywords:  glutaminolysis; glycolysis; metabolism; virus

DOI:  https://doi.org/10.1002/rmv.2505
J Inflamm Res. 2024 ;17 469-485

Angiotensin-(1-7) Modulates the Warburg Effect to Alleviate Inflammation in LPS-Induced Macrophages and Septic Mice.

Dan Yu, Wenhan Huang, Min Sheng, Shan Zhang, Hang Pan, Feifeng Ren, Lei Luo, Jun Zhou, Dongmei Huang, Lin Tang.

   Purpose: Inflammation triggers a metabolic shift in macrophages from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg effect. This metabolic reprogramming worsens inflammation and cascades into organ damage. Angiotensin-(1-7) [Ang-(1-7)], a small molecule, has demonstrated anti-inflammatory properties. This study investigates whether Ang-(1-7) mitigates inflammation in LPS-induced macrophages and septic mice by regulating the Warburg effect in immune metabolism.
Methods: The study induced macrophages with LPS in vitro and measured inflammatory factors using ELISA and Western blot. Key enzymes in glycolysis, mitochondrial respiratory complexes, and citrate pathway key molecules were assessed using Western blot and qRT-PCR. Mitochondrial membrane potential (MMP), lactate, and ATP were measured using assay kits. In vivo, a mouse model of sepsis induced by LPS was used. Kidney tissues were examined for pathological and mitochondrial ultrastructural alterations. The levels of inflammatory factors in mouse serum, glycolysis and citrate pathway-related molecules in the kidney were assessed using qRT-PCR, Western blot, and immunofluorescence techniques. Additionally, MMP, lactate, and ATP in the kidney were measured using assay kits.
Results: In vitro experiments demonstrated that Ang-(1-7) inhibited the levels of inflammatory factors in LPS-treated RAW264.7 cells. It also reduced the expression of key glycolytic enzymes HK2, PFKFB3, and PKM2, as well as lactate levels. Additionally, it decreased intracellular citrate accumulation, enhanced mitochondrial respiratory complexes I and III, and ATP levels. Ang-(1-7) alleviated MMP damage, modulated citrate pathway-related molecules, including SLC25A1, ACLY, and HIF-1α. In vivo experiments showed that Ang-(1-7) lowered glycolysis levels in septic mice, improved mitochondrial ultrastructure and function, mitigated inflammation and renal tissues damage in septic mice, and suppressed the expression of key molecules in the citrate pathway.
Conclusion: In conclusion, Ang-(1-7) can regulate the Warburg effect through the citrate pathway, thereby alleviating inflammation in LPS-induced macrophages and septic mice.

Keywords:  Ang-(1-7); Warburg effect; citrate; glycolysis; macrophage; sepsis

DOI:  https://doi.org/10.2147/JIR.S446013
Clin Immunol. 2024 Jan 28. pii: S1521-6616(24)00026-3. [Epub ahead of print]260 109915

IKAROS expression drives the aberrant metabolic phenotype of macrophages in chronic HIV infection.

Cecilia Vittori, Celeste Faia, Dorota Wyczechowska, Amber Trauth, Karlie Plaisance-Bonstaff, Mary Meyaski-Schluter, Krzysztof Reiss, Francesca Peruzzi.

  The increased risk for acquiring secondary illnesses in people living with HIV (PLWH) has been associated with immune dysfunction. We have previously found that circulating monocytes from PLWH display a trained phenotype. Here, we evaluated the metabolic profile of these cells and found increased mitochondrial respiration and glycolysis of monocyte-derived macrophages (MDMs) from PLWH. We additionally found that cART shifted the energy metabolism of MDMs from controls toward increased utilization of mitochondrial respiration. Importantly, both downregulation of IKAROS expression and inhibition of the mTOR pathway reversed the metabolic profile of MDMs from PLWH and cART-treated control-MDMs. Altogether, this study reveals a very specific metabolic adaptation of MDMs from PLWH, which involves an IKAROS/mTOR-dependent increase of mitochondrial respiration and glycolysis. We propose that this metabolic adaptation decreases the ability of these cells to respond to environmental cues by "locking" PLWH monocytes in a pro-inflammatory and activated phenotype.

Keywords:  Cell metabolism; HIV; Human monocytes; IKAROS

DOI:  https://doi.org/10.1016/j.clim.2024.109915
PLoS Negl Trop Dis. 2024 Feb 02. 18(2): e0011923

Metabolomic landscape of macrophage discloses an anabolic signature of dengue virus infection and antibody-dependent enhancement of viral infection.

Li Xu, Min Li, Jingpu Zhang, Dongxiao Li, Jie Tao, Fuchun Zhang, Xia Jin, Jiahai Lu, Tiefu Liu.

Dengue virus (DENV) infection causes dengue fever, the most prevalent arthropod-transmitted viral disease worldwide. Viruses are acellular parasites and obligately rely on host cell machinery for reproduction. Previous studies have indicated metabolomic changes in endothelial cell models and sera of animal models and patients with dengue fever. To probe the immunometabolic mechanism of DENV infection, here, we report the metabolomic landscape of a human macrophage cell model of DENV infection and its antibody-dependent enhancement. DENV infection of THP-1-derived macrophages caused 202 metabolic variants, of which amino acids occupied 23.7%, fatty acids 21.78%, carbohydrates 10.4%, organic acids 13.37%, and carnitines 10.4%. These metabolomic changes indicated an overall anabolic signature, which was characterized by the global exhaustion of amino acids, increases of cellular fatty acids, carbohydrates and pentoses, but decreases of acylcarnitine. Significant activation of metabolic pathways of glycolysis, pentose phosphate, amino acid metabolism, and tricarboxylic acid cycle collectively support the overall anabolism to meet metabolic demands of DENV replication and immune activation by viral infection. Totally 88 of 202 metabolic variants were significantly changed by DENV infection, 36 of which met the statistical standard (P<0.05, VIP>1.5) of differentially expressed metabolites, which were the predominantly decreased variants of acylcarnitine and the increased variants of fatty acids and carbohydrates. Remarkably, 11 differentially expressed metabolites were significantly distinct between DENV only infection and antibody-dependent enhancement of viral infection. Our data suggested that the anabolic activation by DENV infection integrates the viral replication and anti-viral immune activation.

DOI: https://doi.org/10.1371/journal.pntd.0011923
Microbiol Mol Biol Rev. 2024 Feb 01. e0016422

The intersection of host in vivo metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites.

Sarah Ewald, Azadeh Nasuhidehnavi, Tzu-Yu Feng, Mahbobeh Lesani, Laura-Isobel McCall.

  SUMMARYProtozoan parasite infection dramatically alters host metabolism, driven by immunological demand and parasite manipulation strategies. Immunometabolic checkpoints are often exploited by kinetoplastid and protozoan parasites to establish chronic infection, which can significantly impair host metabolic homeostasis. The recent growth of tools to analyze metabolism is expanding our understanding of these questions. Here, we review and contrast host metabolic alterations that occur in vivo during infection with Leishmania, trypanosomes, Toxoplasma, Plasmodium, and Cryptosporidium. Although genetically divergent, there are commonalities among these pathogens in terms of metabolic needs, induction of the type I immune responses required for clearance, and the potential for sustained host metabolic dysbiosis. Comparing these pathogens provides an opportunity to explore how transmission strategy, nutritional demand, and host cell and tissue tropism drive similarities and unique aspects in host response and infection outcome and to design new strategies to treat disease.

Keywords:  Cryptosporidium; Leishmania; Plasmodium; Toxoplasma gondii; Trypanosoma; apicomplexan; host-parasite relationship; immunity; kinetoplastida; metabolism

DOI:  https://doi.org/10.1128/mmbr.00164-22
Nat Commun. 2024 Jan 27. 15(1): 807

Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.

Ting Dong, Guangan Hu, Zhongqi Fan, Huirui Wang, Yinghui Gao, Sisi Wang, Hao Xu, Michael B Yaffe, Matthew G Vander Heiden, Guoyue Lv, Jianzhu Chen.

Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes. In mice, GPR3 activation in Kupffer cells results in enhanced glycolysis, reduced inflammation and inhibition of high-fat diet induced obesity and liver pathogenesis. In human fatty liver biopsies, GPR3 activation increases expression of glycolytic genes and reduces expression of inflammatory genes in a population of disease-associated macrophages. These findings identify GPR3 activation as a pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.

DOI: https://doi.org/10.1038/s41467-024-45167-5
Cell Death Dis. 2024 Feb 01. 15(2): 105

ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.

Tanja Eberhart, Federico Uchenna Stanley, Luisa Ricci, Tiziana Chirico, Roberto Ferrarese, Sofia Sisti, Alessandra Scagliola, Andreina Baj, Sylvia Badurek, Andreas Sommer, Rachel Culp-Hill, Monika Dzieciatkowska, Engy Shokry, David Sumpton, Angelo D'Alessandro, Nicola Clementi, Nicasio Mancini, Simone Cardaci.

Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.

DOI: https://doi.org/10.1038/s41419-024-06483-2
Cell Rep Med. 2024 Jan 30. pii: S2666-3791(24)00009-0. [Epub ahead of print] 101400

Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism.

Yue Huang, Mi Shao, Xinyi Teng, Xiaohui Si, Longyuan Wu, Penglei Jiang, Lianxuan Liu, Bohan Cai, Xiujian Wang, Yingli Han, Youqin Feng, Kai Liu, Zhaoru Zhang, Jiazhen Cui, Mingming Zhang, Yongxian Hu, Pengxu Qian, He Huang.

  Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with in vitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca2+ signaling and activation of the CD38-NAD+-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.

Keywords:  CAR-T; CD38; SIRT1; cADPR; chimeric antigen receptor T; exhaustion; glycolysis

DOI:  https://doi.org/10.1016/j.xcrm.2024.101400
J Hematol Oncol. 2024 Jan 31. 17(1): 6

Metabolic reprogramming in the tumor microenvironment of liver cancer.

Jian Lin, Dongning Rao, Mao Zhang, Qiang Gao.

  The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.

Keywords:  Gut–liver axis; Immune microenvironment; Liver cancer; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s13045-024-01527-8
Immunometabolism (Cobham). 2024 Jan;6(1): e00036

The emerging role for neutrophil mitochondrial metabolism in lung inflammation.

Mary E Maldarelli, Michael J Noto.

  Recent advances shed light on the importance of mitochondrial metabolism in supporting essential neutrophil functions such as trafficking, NETosis, bacterial killing, and modulating inflammatory responses. Mitochondrial metabolism is now recognized to contribute to a number of lung diseases marked by neutrophilic inflammation, including bacterial pneumonia, acute lung injury, and chronic obstructive pulmonary disease. In this mini review, we provide an overview of neutrophil metabolism focusing on the role of mitochondrial programs, discuss select neutrophil effector functions that are directly influenced by mitochondrial metabolism, and present what is known about the role for mitochondrial metabolism in lung diseases marked by neutrophilic inflammation.

Keywords:  infection; inflammation; lung; mitochondrial metabolism; neutrophil; pulmonary

DOI:  https://doi.org/10.1097/IN9.0000000000000036
Eur J Immunol. 2024 Jan 28. e2350800

Composition of fatty acids in a high-fat diet affects adipose tissue inflammation by inducing calreticulin on adipocytes and activating group 1 innate lymphoid cells.

Kazunori Matsumura, Taizo Mori, Taeko Dohi, Yuki I Kawamura, Satoshi Takaki.

  Obesity-induced adipose tissue inflammation plays a critical role in the development of metabolic diseases. For example, NK1.1+ group 1 innate lymphoid cells (G1-ILCs) in adipose tissues are activated in the early stages of inflammation in response to a high-fat diet (HFD). In this study, we examined whether the composition of fatty acids affected adipose inflammatory responses induced by an HFD. Mice were fed a stearic acid (C18:0)-rich HFD (HFD-S) or a linoleic acid (C18:2)-rich HFD (HFD-L). HFD-L-fed mice showed significant obesity compared with HFD-S-fed mice. Visceral and subcutaneous fat pads were enlarged and contained more NK1.1+ KLRG1+ cells, indicating that G1-ILCs were activated in HFD-L-fed mice. We examined early changes in adipose tissues during the first week of HFD intake, and found that mice fed HFD-L showed increased levels of NK1.1+ CD11b+ KLRG1+ cells in adipose tissues. In adipose tissue culture, addition of 4-hydroxynonenal, the most frequent product of lipid peroxidation derived from unsaturated fatty acids, induced NK1.1+ CD11b+ CD27- cells. We found that calreticulin, a ligand for the NK activating receptor, was induced on the surface of adipocytes after exposure to 4-hydroxynonenal or a 1-week feeding with HFD-L. Thus, excess fatty acid intake and the activation of G1-ILCs initiate and/or modify adipose inflammation.

Keywords:  Adipose tissue inflammation; High-fat diet; Innate lymphoid cells; NK cells; Obesity

DOI:  https://doi.org/10.1002/eji.202350800
Nat Commun. 2024 Feb 01. 15(1): 966

Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.

Rui Sun, Chao Lei, Zhishan Xu, Xuemei Gu, Liu Huang, Liang Chen, Yi Tan, Min Peng, Kavitha Yaddanapudi, Leah Siskind, Maiying Kong, Robert Mitchell, Jun Yan, Zhongbin Deng.

The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.

DOI: https://doi.org/10.1038/s41467-024-45084-7
Front Immunol. 2023 ;14 1270268

Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.

Rima Elhage, Mairead Kelly, Nicolas Goudin, Jérôme Megret, Agnès Legrand, Ivan Nemazanyy, Cécilia Patitucci, Véronique Quellec, Timothy Wai, Ahmed Hamaï, Sophie Ezine.

  Several studies demonstrated that mitochondrial dynamics and metabolic pathways control T cell fate in the periphery. However, little is known about their implication in thymocyte development. Our results showed that thymic progenitors (CD3-CD4-CD8- triple negative, TN), in active division, have essentially a fused mitochondrial morphology and rely on high glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). As TN cells differentiate to double positive (DP, CD4+CD8+) and single positive (SP, CD4+ and CD8+) stages, they became more quiescent, their mitochondria fragment and they downregulate glycolysis and OXPHOS. Accordingly, in vitro inhibition of the mitochondrial fission during progenitor differentiation on OP9-DL4 stroma, affected the TN to DP thymocyte transition by enhancing the percentage of TN and reducing that of DP, leading to a decrease in the total number of thymic cells including SP T cells. We demonstrated that the stage 3 triple negative pre-T (TN3) and the stage 4 triple negative pre-T (TN4) have different metabolic and functional behaviors. While their mitochondrial morphologies are both essentially fused, the LC-MS based analysis of their metabolome showed that they are distinct: TN3 rely more on OXPHOS whereas TN4 are more glycolytic. In line with this, TN4 display an increased Hexokinase II expression in comparison to TN3, associated with high proliferation and glycolysis. The in vivo inhibition of glycolysis using 2-deoxyglucose (2-DG) and the absence of IL-7 signaling, led to a decline in glucose metabolism and mitochondrial membrane potential. In addition, the glucose/IL-7R connection affects the TN3 to TN4 transition (also called β-selection transition), by enhancing the percentage of TN3, leading to a decrease in the total number of thymocytes. Thus, we identified additional components, essential during β-selection transition and playing a major role in thymic development.

Keywords:  OxPhos; T cell progenitors; glycolysis; metabolome; mitochondrial dynamics; thymus; β-selection checkpoint

DOI:  https://doi.org/10.3389/fimmu.2023.1270268
Cell Rep. 2024 Jan 30. pii: S2211-1247(24)00052-4. [Epub ahead of print]43(2): 113724

p53 promotes antiviral innate immunity by driving hexosamine metabolism.

Wenjun Xia, Peng Jiang.

  The tumor suppressor p53 controls cell fate decisions and prevents malignant transformation, but its functions in antiviral immunity remain unclear. Here, we demonstrate that p53 metabolically promotes antiviral innate immune responses to RNA viral infection. p53-deficient macrophages or mice display reduced expression of glutamine fructose-6-phosphate amidotransferase 2 (GFPT2), a key enzyme of the hexosamine biosynthetic pathway (HBP). Through transcriptional upregulation of GFPT2, p53 drives HBP activity and de novo synthesis of UDP-GlcNAc, which in turn leads to the O-GlcNAcylation of mitochondrial antiviral signaling protein (MAVS) and UBX-domain-containing protein 1 (UBXN1) during virus infection. Moreover, O-GlcNAcylation of UBXN1 blocks its interaction with MAVS, thereby further liberating MAVS for tumor necrosis factor receptor-associated factor 3 binding to activate TANK-binding kinase 1-interferon (IFN) regulatory factor 3 signaling cascades and IFN-β production. Genetic or pharmaceutical inhibition of GFPT efficiently reduces MAVS activation and abrogates the antiviral innate immunity promoted by p53 in vitro and in vivo. Our findings reveal that p53 drives HBP activity and O-GlcNAcylation of UBXN1 and MAVS to enhance IFN-β-mediated antiviral innate immunity.

Keywords:  CP: Cell biology; CP: Immunology; O-GlcNAcylation; UBXN1-MAVS signaling; antiviral innate immunity; hexosamine metabolism; tumor suppressor p53

DOI:  https://doi.org/10.1016/j.celrep.2024.113724
mBio. 2024 Jan 30. e0253523

Exogenous butyrate inhibits butyrogenic metabolism and alters virulence phenotypes in Clostridioides difficile.

Daniel A Pensinger, Horia A Dobrila, David M Stevenson, Nicole D Hryckowian, Daniel Amador-Noguez, Andrew J Hryckowian.

  The gut microbiome engenders colonization resistance against the diarrheal pathogen Clostridioides difficile, but the molecular basis of this colonization resistance is incompletely understood. A prominent class of gut microbiome-produced metabolites important for colonization resistance against C. difficile is short-chain fatty acids (SCFAs). In particular, one SCFA (butyrate) decreases the fitness of C. difficile in vitro and is correlated with C. difficile-inhospitable gut environments, both in mice and in humans. Here, we demonstrate that butyrate-dependent growth inhibition in C. difficile occurs under conditions where C. difficile also produces butyrate as a metabolic end product. Furthermore, we show that exogenous butyrate is internalized into C. difficile cells and is incorporated into intracellular CoA pools where it is metabolized in a reverse (energetically unfavorable) direction to crotonyl-CoA and (S)-3-hydroxybutyryl-CoA and/or 4-hydroxybutyryl-CoA. This internalization of butyrate and reverse metabolic flow of a butyrogenic pathway(s) in C. difficile coincides with alterations in toxin release and sporulation. Together, this work highlights butyrate as a marker of a C. difficile-inhospitable environment to which C. difficile responds by releasing its diarrheagenic toxins and producing environmentally resistant spores necessary for transmission between hosts. These findings provide foundational data for understanding the molecular and genetic basis of how C. difficile growth is inhibited by butyrate and how butyrate alters C. difficile virulence in the face of a highly competitive and dynamic gut environment.IMPORTANCEThe gut microbiome engenders colonization resistance against the diarrheal pathogen Clostridioides difficile, but the molecular basis of this colonization resistance is incompletely understood, which hinders the development of novel therapeutic interventions for C. difficile infection (CDI). We investigated how C. difficile responds to butyrate, an end-product of gut microbiome community metabolism which inhibits C. difficile growth. We show that exogenously produced butyrate is internalized into C. difficile, which inhibits C. difficile growth by interfering with its own butyrate production. This growth inhibition coincides with increased toxin release from C. difficile cells and the production of environmentally resistant spores necessary for transmission between hosts. Future work to disentangle the molecular mechanisms underlying these growth and virulence phenotypes will likely lead to new strategies to restrict C. difficile growth in the gut and minimize its pathogenesis during CDI.

Keywords:  enteric pathogens; gram-positive bacteria; metabolism; pathogenesis

DOI:  https://doi.org/10.1128/mbio.02535-23
J Clin Invest. 2024 Jan 30. pii: e170848. [Epub ahead of print]

MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.

Rutger J Röring, Priya A Debisarun, Javier Botey-Bataller, Tsz Kin Suen, Ozlem Bulut, Gizem Kilic, Valerie Acm Koeken, Andrei Sarlea, Harsh Bahrar, Helga Dijkstra, Heidi Lemmers, Katharina L Gössling, Nadine Rüchel, Philipp N Ostermann, Lisa Müller, Heiner Schaal, Ortwin Adams, Arndt Borkhardt, Yavuz Ariyurek, Emile J de Meijer, Susan L Kloet, Jaap Ten Oever, Katarzyna Placek, Yang Li, Mihai G Netea.

  The measles, mumps and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. By using single-cell RNA-sequencing, we found that MMR caused transcriptomic changes in CD14-positive monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFNγ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.

Keywords:  Cellular immune response; Immunology; Innate immunity

DOI:  https://doi.org/10.1172/JCI170848
Cell Host Microbe. 2024 Jan 24. pii: S1931-3128(24)00008-8. [Epub ahead of print]

Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase.

Ju-Sim Kim, Lin Liu, Sashi Kant, David J Orlicky, Siva Uppalapati, Alyssa Margolis, Bennett J Davenport, Thomas E Morrison, Jennifer Matsuda, Michael McClelland, Jessica Jones-Carson, Andres Vazquez-Torres.

  Intracellular Salmonella experiencing oxidative stress downregulates aerobic respiration. To maintain cellular energetics during periods of oxidative stress, intracellular Salmonella must utilize terminal electron acceptors of lower energetic value than molecular oxygen. We show here that intracellular Salmonella undergoes anaerobic respiration during adaptation to the respiratory burst of the phagocyte NADPH oxidase in macrophages and in mice. Reactive oxygen species generated by phagocytes oxidize methionine, generating methionine sulfoxide. Anaerobic Salmonella uses the molybdenum cofactor-containing DmsABC enzymatic complex to reduce methionine sulfoxide. The enzymatic activity of the methionine sulfoxide reductase DmsABC helps Salmonella maintain an alkaline cytoplasm that supports the synthesis of the antioxidant hydrogen sulfide via cysteine desulfuration while providing a source of methionine and fostering redox balancing by associated dehydrogenases. Our investigations demonstrate that nontyphoidal Salmonella responding to oxidative stress exploits the anaerobic metabolism associated with dmsABC gene products, a pathway that has accrued inactivating mutations in human-adapted typhoidal serovars.

Keywords:  Salmonella; anaerobiosis; metabolism; oxidative stress; pathogenesis; phagocyte NADPH oxidase; respiration; sulfur; terminal acceptors

DOI:  https://doi.org/10.1016/j.chom.2024.01.004
Proc Natl Acad Sci U S A. 2024 Feb 06. 121(6): e2320383121

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Ze Cao, Xia Min, Xingxing Xie, Maoqing Huang, Yingying Liu, Weimin Sun, Guifang Xu, Miao He, Kaiwen He, Ying Li, Junying Yuan.

  Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Keywords:  Mecp2; RIPK1; RTT; inflammation; microglia

DOI:  https://doi.org/10.1073/pnas.2320383121