bims-imicid 2023-12-03 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒12‒03
forty-four papers selected by
Dylan Ryan, University of Cambridge

Fluoxetine promotes immunometabolic defenses to mediate host-pathogen cooperation during sepsis.
The evolutionary tug-of-war of macrophage metabolism during bacterial infection.
Role of immunometabolism during congenital cytomegalovirus infection.
Therapeutic targeting of immunometabolism in Alzheimer's disease reveals a critical reliance on Hexokinase 2 dosage on microglial activation and disease progression.
Metabolic influences on T cell in psoriasis: a literature review.
IL-17A Orchestrates Reactive Oxygen Species/HIF1α-Mediated Metabolic Reprogramming in Psoriasis.
Treponema pallidum recombinant protein Tp47 activates NOD-like receptor family protein 3 inflammasomes in macrophages via glycolysis.
Lipid metabolism in B cell biology.
Macrophage AMPK β1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice.
Itaconate as a key regulator of respiratory disease.
Uncoupling protein 2 modulates polarization and metabolism of human primary macrophages via glycolysis and the NF‑κB pathway.
Metabolic immunity against microbes.
Metabolism shapes immune responses to Staphylococcus aureus.
ACC1-mediated fatty acid biosynthesis intrinsically controls thymic iNKT cell development.
Identification of proteome-based immune subtypes of early hepatocellular carcinoma and analysis of potential metabolic drivers.
Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance.
Impact of intestinal microenvironments in obesity and bariatric surgery on shaping macrophages.
Nur77 influences immunometabolism to regulate the release of proinflammatory cytokines and the formation of lipid bodies during Mycobacterium tuberculosis infection of macrophages.
Host-pathogen interactions from a metabolic perspective: methods of investigation.
2-Deoxy-D-glucose ameliorates inflammation and fibrosis in a silicosis mouse model by inhibiting hypoxia-inducible factor-1α in alveolar macrophages.
The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.
Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH.
Dectin-2 Deficiency Promotes Pro-inflammatory Cytokine Release from Macrophages and Impairs Insulin Secretion.
PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.
Effect of triggering receptor expressed on myeloid cells 2-associated alterations on lipid metabolism in macrophages in the development of non-alcoholic fatty liver disease.
Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment.
Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.
Butyrate induces oxidative burst mediated apoptosis via Glucose-6-Phosphate Dehydrogenase (G6PDH) in macrophages during mycobacterial infection.
Lactobacillus-derived indole-3-lactic acid ameliorates colitis in cesarean-born offspring via activation of aryl hydrocarbon receptor.
Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis.
Metformin mitigates sepsis-associated pulmonary fibrosis by promoting AMPK activation and inhibiting Hif-1α-induced aerobic glycolysis.
ATP-dependent transporters: emerging players at the crossroads of immunity and metabolism.
Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment.
The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
SEMA4D/VEGF surface enhances endothelialization by diminished-glycolysis-mediated M2-like macrophage polarization.
Restoring the infected powerhouse: Mitochondrial quality control in sepsis.
Impact of norepinephrine on immunity and oxidative metabolism in sepsis.
The Microbial Tryptophan Metabolite Contributes to the Remission of Salmonella typhimurium Infection in Mice.
Disturbance of Adaptive Immunity System Was Accompanied by a Decrease in Plasma Short-Chain Fatty Acid for Patients Hospitalized During SARS-CoV-2 Infection After COVID-19 Vaccination.
Disruption of cholesterol homeostasis triggers periodontal inflammation and alveolar bone loss.
Metabolomic profiling of Marek's disease virus infection in host cell based on untargeted LC-MS.

bioRxiv. 2023 Nov 18. pii: 2023.11.18.567681. [Epub ahead of print]

Fluoxetine promotes immunometabolic defenses to mediate host-pathogen cooperation during sepsis.

Robert M Gallant, Jessica M Snyder, Janelle S Ayres.

Selective serotonin reuptake inhibitors (SSRIs) are some of the most prescribed drugs in the world. While they are used for their ability to increase serotonergic signaling in the brain, SSRIs are also known to have a broad range of effects beyond the brain, including immune and metabolic effects. Recent studies have demonstrated that SSRIs are protective in animal models and humans against several infections, including sepsis and COVID-19, however the mechanisms underlying this protection are largely unknown. Here we mechanistically link two previously described effects of the SSRI fluoxetine in mediating protection against sepsis. We show that fluoxetine-mediated protection is independent of peripheral serotonin, and instead increases levels of circulating IL-10. IL-10 is necessary for protection from sepsis-induced hypertriglyceridemia and cardiac triglyceride accumulation, allowing for metabolic reprogramming of the heart. Our work reveals a beneficial "off-target" effect of fluoxetine, and reveals a protective immunometabolic defense mechanism with therapeutic potential.

DOI: https://doi.org/10.1101/2023.11.18.567681
Trends Endocrinol Metab. 2023 Nov 30. pii: S1043-2760(23)00241-2. [Epub ahead of print]

The evolutionary tug-of-war of macrophage metabolism during bacterial infection.

Luís Almeida, Ayesha Dhillon-LaBrooy, Tim Sparwasser.

  The function and phenotype of macrophages are intimately linked with pathogen detection. On sensing pathogen-derived signals and molecules, macrophages undergo a carefully orchestrated process of polarization to acquire pathogen-clearing properties. This phenotypic change must be adequately supported by metabolic reprogramming that is now known to support the acquisition of effector function, but also generates secondary metabolites with direct microbicidal activity. At the same time, bacteria themselves have adapted to both manipulate and take advantage of macrophage-specific metabolic adaptations. Here, we summarize the current knowledge on macrophage metabolism during infection, with a particular focus on understanding the 'arms race' between host immune cells and bacteria during immune responses.

Keywords:  bacterial metabolism; host–pathogen interactions; immunometabolism; infection; macrophage metabolism

DOI:  https://doi.org/10.1016/j.tem.2023.11.002
Immunometabolism (Cobham). 2023 Oct;5(4): e00034

Role of immunometabolism during congenital cytomegalovirus infection.

Kevin J Zwezdaryk, Amitinder Kaur.

  Cytomegalovirus (CMV) is a master manipulator of host metabolic pathways. The impact of CMV metabolic rewiring during congenital CMV on immune function is unknown. CMV infection can directly alter glycolytic and oxidative phosphorylation pathways in infected cells. Recent data suggests CMV may alter metabolism in uninfected neighboring cells. In this mini review, we discuss how CMV infection may impact immune function through metabolic pathways. We discuss how immune cells differ between maternal and decidual compartments and how altered immunometabolism may contribute to congenital infections.

Keywords:  congenital cytomegalovirus; immunometabolism; placenta

DOI:  https://doi.org/10.1097/IN9.0000000000000034
bioRxiv. 2023 Nov 15. pii: 2023.11.11.566270. [Epub ahead of print]

Therapeutic targeting of immunometabolism in Alzheimer's disease reveals a critical reliance on Hexokinase 2 dosage on microglial activation and disease progression.

Juan F Codocedo, Claudia Mera-Reina, Peter Bor-Chian Lin, Shweta S Puntambekar, Brad T Casali, Nur Jury, Pablo Martinez, Cristian A Lasagna-Reeves, Gary E Landreth.

Microgliosis and neuroinflammation are prominent features of Alzheimer's disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFKβ signaling, through its cytosolic target IKBα. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction.Highlights: Hexokinase 2, the first and rate-limiting enzyme of glycolysis, is specifically upregulated in plaque-associated microglia of AD mice models and in the postmortem cortex of human AD patients.Microglia haploinsufficient in HK2 exhibit reduced amyloid burden and inflammation as well as improved cognition in a mouse model of AD. Paradoxically, the complete loss of HK2 results in opposite effects, by exacerbating inflammation.Lonidamine, an anticancer drug that inhibits HK2, mimics the salutary effects of HK2 haploinsufficiency in the 5xFAD mice, but only in males during the early stages of disease.HK2 deletion induced mitochondrial dysfunction associated to increased expression of inflammasome elements and IL-1β.HK2 partial antagonism exerts beneficial effects independent of its energetic or mitochondrial role, likely through cytosolic stabilization of IκBα and inhibition of the NF-κB pathway, leading to reduced proinflammatory gene expression.

DOI: https://doi.org/10.1101/2023.11.11.566270
Front Immunol. 2023 ;14 1279846

Metabolic influences on T cell in psoriasis: a literature review.

Rina Su, Siqi Zhao, Jinqing Zhang, Mei Cao, Shiguang Peng.

  Psoriasis is a systemic inflammatory disease that frequently coexists with various other conditions, such as essential hypertension, diabetes, metabolic syndrome, and inflammatory bowel disease. The association between these diseases may be attributed to shared inflammatory pathways and abnormal immunomodulatory mechanisms. Furthermore, metabolites also play a regulatory role in the function of different immune cells involved in psoriasis pathogenesis, particularly T lymphocytes. In this review, we have summarized the current research progress on T cell metabolism in psoriasis, encompassing the regulation of metabolites in glucose metabolism, lipid metabolism, amino acid metabolism, and other pathways within T cells affected by psoriasis. We will also explore the interaction and mechanism between psoriatic metabolites and immune cells. Moreover, we further discussed the research progress of metabolomics in psoriasis to gain a deeper understanding of its pathogenesis and identify potential new therapeutic targets through identification of metabolic biomarkers associated with this condition.

Keywords:  T cell; amino acid metabolism; glucose metabolism; lipid metabolism; psoriasis

DOI:  https://doi.org/10.3389/fimmu.2023.1279846
J Immunol. 2023 Nov 29. pii: ji2300319. [Epub ahead of print]

IL-17A Orchestrates Reactive Oxygen Species/HIF1α-Mediated Metabolic Reprogramming in Psoriasis.

Bhavuk Dhamija, Soumitra Marathe, Vinanti Sawant, Moumita Basu, Diksha Attrish, Ditipriya Mukherjee, Sushant Kumar, Medha Gayathri J Pai, Siddhi Wad, Abhijeet Sawant, Chitra Nayak, Kareenhalli V Venkatesh, Sanjeeva Srivastava, Steven R Barthel, Rahul Purwar.

Immune cell-derived IL-17A is one of the key pathogenic cytokines in psoriasis, an immunometabolic disorder. Although IL-17A is an established regulator of cutaneous immune cell biology, its functional and metabolic effects on nonimmune cells of the skin, particularly keratinocytes, have not been comprehensively explored. Using multiomics profiling and systems biology-based approaches, we systematically uncover significant roles for IL-17A in the metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy revealed IL-17A-dependent regulation of multiple HPK proteins and metabolites of carbohydrate and lipid metabolism. Systems-level MitoCore modeling using flux-balance analysis identified IL-17A-mediated increases in HPK glycolysis, glutaminolysis, and lipid uptake, which were validated using biochemical cell-based assays and stable isotope-resolved metabolomics. IL-17A treatment triggered downstream mitochondrial reactive oxygen species and HIF1α expression and resultant HPK proliferation, consistent with the observed elevation of these downstream effectors in the epidermis of patients with psoriasis. Pharmacological inhibition of HIF1α or reactive oxygen species reversed IL-17A-mediated glycolysis, glutaminolysis, lipid uptake, and HPK hyperproliferation. These results identify keratinocytes as important target cells of IL-17A and reveal its involvement in multiple downstream metabolic reprogramming pathways in human skin.

DOI: https://doi.org/10.4049/jimmunol.2300319
Int Immunopharmacol. 2023 Nov 27. pii: S1567-5769(23)01531-X. [Epub ahead of print]126 111204

Treponema pallidum recombinant protein Tp47 activates NOD-like receptor family protein 3 inflammasomes in macrophages via glycolysis.

Xin-Qi Zheng, Ze Li, Qing-Qi Meng, Wei Li, Qiu-Ling Li, Lin Xie, Yao Xiao, Qiu-Yan Xu, Yu-Yan Chen.

  Glycolysis is a key pathway in cellular glucose metabolism for energy supply and regulates immune cell activation. Whether glycolysis is involved in the activation of NOD-like receptor family protein 3 (NLRP3) inflammasomes during Treponema pallidum (T. pallidum) infection is unclear. In this study, the effect of T. pallidum membrane protein Tp47 on NLRP3 inflammasome activation in rabbit peritoneal macrophages was analysed and the role of glycolysis in NLRP3 inflammasome activation was explored. The results showed that Tp47 promoted NLRP3, caspase-1, and IL-1β mRNA expression in macrophages, enhanced glycolysis and glycolytic capacity of macrophage, and promoted the production of macrophage glycolytic metabolites citrate, phosphoenolpyruvate, and lactate. The M2 pyruvate kinase (PKM2) inhibitor shikonin down-regulated the Tp47-promoted NLRP3, caspase-1, and IL-1β mRNA expression in macrophages, and suppressed the Tp47-enhanced glycolysis and glycolytic capacity. Similarly, si-PKM2 significantly inhibited Tp47-promoted NLRP3, caspase-1, and IL-1β mRNA expression and the Tp47-enhanced glycolysis and glycolytic capacity in macrophages. In conclusion, Tp47 activated NLRP3 inflammasomes via PKM2-dependent glycolysis and provided a new perspective on the effect of T. pallidum infection on host macrophages, which would contribute to the understanding of the infection mechanism and host immune mechanism of T. pallidum.

Keywords:  Glycolysis; Macrophage; NLRP3 inflammasome; Tp47; Treponema pallidum

DOI:  https://doi.org/10.1016/j.intimp.2023.111204
Mol Oncol. 2023 Nov 27.

Lipid metabolism in B cell biology.

Rens Peeters, Julia Jellusova.

  In recent years, the field of immunometabolism has solidified its position as a prominent area of investigation within the realm of immunological research. An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signaling molecules, and metabolites in relation to fundamental aspects of our immune cells. It is now widely accepted that disruptions in metabolic equilibrium can give rise to a myriad of pathological conditions, ranging from autoimmune disorders to cancer. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behavior of immune cells, including B cells. In light of these findings, this review aims to provide a comprehensive overview of the current state of knowledge regarding lipid metabolism in the context of B cell biology.

Keywords:  B cell development; B cell malignancies; B cells; Immunometabolism; Lipid metabolism; Lipid signaling

DOI:  https://doi.org/10.1002/1878-0261.13560
iScience. 2023 Nov 17. 26(11): 108269

Macrophage AMPK β1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice.

Emily A Day, Logan K Townsend, Sonia Rehal, Battsetseg Batchuluun, Dongdong Wang, Marisa R Morrow, Rachel Lu, Lucie Lundenberg, Jessie H Lu, Eric M Desjardins, Tyler K T Smith, Amogelang R Raphenya, Andrew G McArthur, Morgan D Fullerton, Gregory R Steinberg.

  Atherosclerotic cardiovascular disease is characterized by both chronic low-grade inflammation and dyslipidemia. The AMP-activated protein kinase (AMPK) inhibits cholesterol synthesis and dampens inflammation but whether pharmacological activation reduces atherosclerosis is equivocal. In the current study, we found that the orally bioavailable and highly selective activator of AMPKβ1 complexes, PF-06409577, reduced atherosclerosis in two mouse models in a myeloid-derived AMPKβ1 dependent manner, suggesting a critical role for macrophages. In bone marrow-derived macrophages (BMDMs), PF-06409577 dose dependently activated AMPK as indicated by increased phosphorylation of downstream substrates ULK1 and acetyl-CoA carboxylase (ACC), which are important for autophagy and fatty acid oxidation/de novo lipogenesis, respectively. Treatment of BMDMs with PF-06409577 suppressed fatty acid and cholesterol synthesis and transcripts related to the inflammatory response while increasing transcripts important for autophagy through AMPKβ1. These data indicate that pharmacologically targeting macrophage AMPKβ1 may be a promising strategy for reducing atherosclerosis.

Keywords:  Immunology

DOI:  https://doi.org/10.1016/j.isci.2023.108269
Clin Exp Immunol. 2023 Nov 29. pii: uxad127. [Epub ahead of print]

Itaconate as a key regulator of respiratory disease.

Christina Michalaki, Gesa J Albers, Adam J Byrne.

  Macrophage activation results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles; one such bioactive metabolite is itaconate. After macrophage stimulation, the TCA-cycle intermediate cis-aconitate is converted to itaconate (by aconitate decarboxylase-1, ACOD1) in the mitochondrial matrix. Recent studies have highlighted the potential of targeting itaconate as a therapeutic strategy for lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and respiratory infections. This review aims to bring together evidence which highlights a role for itaconate in chronic lung diseases (such as asthma and pulmonary fibrosis) and respiratory infections (such as SARS-CoV-2, influenza and Mycobacterium tuberculosis infection). A better understanding of the role of itaconate in lung disease could pave the way for novel therapeutic interventions and improve patient outcomes in respiratory disorders.

Keywords:  Respiratory disease; itaconate; macrophages

DOI:  https://doi.org/10.1093/cei/uxad127
Exp Ther Med. 2023 Dec;26(6): 583

Uncoupling protein 2 modulates polarization and metabolism of human primary macrophages via glycolysis and the NF‑κB pathway.

Liguo Lang, Dongju Zheng, Qingjun Jiang, Ting Meng, Xiaohu Ma, Yang Yang.

  Metabolic abnormalities, particularly the M1/M2 macrophage imbalance, play a critical role in the development of various diseases, leading to severe inflammatory responses. The present study aimed to investigate the role of uncoupling protein 2 (UCP2) in regulating macrophage polarization, glycolysis, metabolic reprogramming, reactive oxygen species (ROS) and inflammation. Primary human macrophages were first polarized into M1 and M2 subtypes, and these two subtypes were infected by lentivirus-mediated UCP2 overexpression or knockdown, followed by enzyme-linked immunosorbent assay, reverse transcription-quantitative PCR, western blotting and flow cytometry to analyze the effects of UCP2 on glycolysis, oxidative phosphorylation (OXPHOS), ROS production and cytokine secretion, respectively. The results demonstrated that UCP2 expression was suppressed in M1 macrophages and increased in M2 macrophages, suggesting its regulatory role in macrophage polarization. UCP2 overexpression decreased macrophage glycolysis, increased OXPHOS, decreased ROS production, and led to the conversion of M1 polarization to M2 polarization. This process involved NF-κB signaling to regulate the secretion profile of cytokines and chemokines and affected the expression of key enzymes of glycolysis and a key factor for maintaining mitochondrial homeostasis (nuclear respiratory factor 1). UCP2 knockdown in M2 macrophages exacerbated inflammation and oxidative stress by promoting glycolysis, which was attenuated by the glycolysis inhibitor 2-deoxyglucose. These findings highlight the critical role of UCP2 in regulating macrophage polarization, metabolism, inflammation and oxidative stress through its effects on glycolysis, providing valuable insights into potential therapeutic strategies for macrophage-driven inflammatory and metabolic diseases.

Keywords:  NF-κB; OXPHOS; UCP2; glycolysis; macrophage polarization

DOI:  https://doi.org/10.3892/etm.2023.12282
Trends Cell Biol. 2023 Nov 28. pii: S0962-8924(23)00231-3. [Epub ahead of print]

Metabolic immunity against microbes.

Sebastian Kreimendahl, Lena Pernas.

  Pathogens, including viruses, bacteria, fungi, and parasites, remodel the metabolism of their host to acquire the nutrients they need to proliferate. Thus, host cells are often perceived as mere exploitable nutrient pools during infection. Mounting reports challenge this perception and instead suggest that host cells can actively reprogram their metabolism to the detriment of the microbial invader. In this review, we present metabolic mechanisms that host cells use to defend against pathogens. We highlight the contribution of domesticated microbes to host defenses and discuss examples of host-pathogen arms races that are derived from metabolic conflict.

Keywords:  infection; metabolic defenses; metabolic immunity; metabolism; microbiota; mitochondria; pathogens

DOI:  https://doi.org/10.1016/j.tcb.2023.10.013
J Innate Immun. 2023 Nov 28.

Metabolism shapes immune responses to Staphylococcus aureus.

Prabhakar Arumugam, Tammy Kielian.

Staphylococcus aureus (S. aureus) is a common cause of hospital- and community-acquired infections that can result in various clinical manifestations ranging from mild to severe disease. The bacterium utilizes different combinations of virulence factors and biofilm formation to establish a successful infection, and the emergence of methicillin- and vancomycin-resistant strains introduces additional challenges for infection management and treatment. Metabolic programming of immune cells regulates the balance of energy requirements for activation and dictates pro- vs. anti-inflammatory function. Recent investigations into metabolic adaptations of leukocytes and S. aureus during infection indicate that metabolic crosstalk plays a crucial role in pathogenesis. Furthermore, S. aureus can modify its metabolic profile to fit an array of niches for commensal or invasive growth. Here we focus on the current understanding of immunometabolism during S. aureus infection and explore how metabolic crosstalk between the host and S. aureus influences disease outcome. We also discuss how key metabolic pathways influence leukocyte responses to other bacterial pathogens when information for S. aureus is not available. A better understanding of how S. aureus and leukocytes adapt their metabolic profiles in distinct tissue niches may reveal novel therapeutic targets to prevent or control invasive infections.

DOI: https://doi.org/10.1159/000535482
Int Immunol. 2023 Dec 02. pii: dxad049. [Epub ahead of print]

ACC1-mediated fatty acid biosynthesis intrinsically controls thymic iNKT cell development.

Toshio Kanno, Keisuke Miyako, Takeru Endo, Satoru Yokoyama, Hikari K Asou, Kazuko Yamada, Osamu Ohara, Toshinori Nakayama, Motoko Y Kimura, Yusuke Endo.

  To meet the energetic requirements associated with activation, proliferation and survival, T cells switch their metabolic signatures from energetically quiescent to activated. However, little is known about the role of metabolic pathway controlling the development of invariant natural killer T (iNKT) cells. In the present study, we found that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid biosynthesis pathway, plays an essential role in the development of iNKT cells in the thymus. Mice lacking T-cell specific ACC1 showed reduced number of iNKT cells with an increased proportion of iNKT cells at immature stages 0 and 1. Furthermore, mixed bone marrow (BM) chimera experiments revealed that T-cell-intrinsic ACC1 expression was selectively important for the development of thymic iNKT cells, especially for the differentiation of NKT1 cell subset. Our single-cell RNA-sequencing (scRNA-seq) data and functional analysis demonstrated that ACC1 is responsible for survival of developing iNKT cells. Thus, these findings highlighted a novel role of ACC1 in controlling thymic iNKT cell development mediated by the control of cell survival.

Keywords:  apoptosis; fatty acid metabolism

DOI:  https://doi.org/10.1093/intimm/dxad049
Mol Cell Proteomics. 2023 Nov 24. pii: S1535-9476(23)00197-4. [Epub ahead of print] 100686

Identification of proteome-based immune subtypes of early hepatocellular carcinoma and analysis of potential metabolic drivers.

Lihong Diao, Mengqi He, Binsheng Xu, Lanhui Chen, Ze Wang, Yuting Yang, Simin Xia, Shengwei Hu, Shuzhen Guo, Dong Li.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, ranking fourth in frequency. The relationship between metabolic reprogramming and immune infiltration has been identified as having a crucial impact on HCC progression. However, a deeper understanding of the interplay between the immune system and metabolism in the HCC microenvironment is required. In this study, we used a proteomic dataset to identify three immune subtypes (IM1-IM3) in HCC, each of which has distinctive clinical, immune, and metabolic characteristics. Among these subtypes, IM3 was found to have the poorest prognosis, with the highest levels of immune infiltration and T-cell exhaustion. Furthermore, IM3 showed elevated glycolysis and reduced bile acid metabolism, which was strongly correlated with CD8 T cell exhaustion and regulatory T-cell accumulation. Our study presents the proteomic immune stratification of HCC, revealing the possible link between immune cells and reprogramming of HCC glycolysis and bile acid metabolism, which may be a viable therapeutic strategy to improve HCC immunotherapy.

DOI: https://doi.org/10.1016/j.mcpro.2023.100686
J Virol. 2023 Nov 27. e0127223

Profiling whole-tissue metabolic reprogramming during cutaneous poxvirus infection and clearance.

Luxin Pei, Kirsten E Overdahl, John P Shannon, Katherine M Hornick, Alan K Jarmusch, Heather D Hickman.

  IMPORTANCE: Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur in vivo during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.

Keywords:  immune response; metabolism; poxvirus

DOI:  https://doi.org/10.1128/jvi.01272-23
Immunometabolism (Cobham). 2023 Oct;5(4): e00033

Impact of intestinal microenvironments in obesity and bariatric surgery on shaping macrophages.

Michael Leyderman, Joel R Wilmore, Timothy Shope, Robert N Cooney, Norifumi Urao.

  Obesity is associated with alterations in tissue composition, systemic cellular metabolism, and low-grade chronic inflammation. Macrophages are heterogenous innate immune cells ubiquitously localized throughout the body and are key components of tissue homeostasis, inflammation, wound healing, and various disease states. Macrophages are highly plastic and can switch their phenotypic polarization and change function in response to their local environments. Here, we discuss how obesity alters the intestinal microenvironment and potential key factors that can influence intestinal macrophages as well as macrophages in other organs, including adipose tissue and hematopoietic organs. As bariatric surgery can induce metabolic adaptation systemically, we discuss the potential mechanisms through which bariatric surgery reshapes macrophages in obesity.

Keywords:  IgA; bariatric surgery; bile acids; gastrointestinal environment; macrophages; metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000033
Pathog Dis. 2023 Nov 28. pii: ftad033. [Epub ahead of print]

Nur77 influences immunometabolism to regulate the release of proinflammatory cytokines and the formation of lipid bodies during Mycobacterium tuberculosis infection of macrophages.

Pankaj Birari, Soumya Mal, Debayan Majumder, Arun Kumar Sharma, Manish Kumar, Troyee Das, Zhumur Ghosh, Kuladip Jana, Umesh D Gupta, Manikuntala Kundu, Joyoti Basu.

Infection of macrophages with Mycobacterium tuberculosis induces innate immune responses designed to clear the invading bacterium. However, bacteria often survive within the intracellular environment by exploiting these responses triggered by macrophages. Here, the role of the orphan nuclear receptor Nur77 (Nr4a1), in regulating the response of macrophages infected with M. tuberculosis, has been delineated. Nur77 is induced early during infection, regulates metabolism by binding directly at the promoter of the TCA cycle enzyme, isocitrate dehydrogenase 2 (IDH2) to act as its repressor, and shifts the balance from a proinflammatory to an anti-inflammatory phenotype Depletion of Nur77 increased transcription of IDH2 and consequently, the levels of intracellular succinate leading to enhanced levels of the proinflammatory cytokine, IL-1β. Further, Nur77 inhibited production of antibacterial nitric oxide and IL-1β in a succinate dehydrogenase (SDH)- dependent manner, suggesting that its induction favors bacterial survival by suppressing bactericidal responses. Indeed, depletion of Nur77 inhibited intracellular survival of M. tuberculosis. On the other hand, depletion of Nur77 enhanced lipid body formation suggesting that the fall in Nur77 levels as infection progresses, likely favors foamy macrophage formation and long-term survival of M. tuberculosis in the host milieu.

DOI: https://doi.org/10.1093/femspd/ftad033
Microbes Infect. 2023 Nov 23. pii: S1286-4579(23)00170-3. [Epub ahead of print] 105267

Host-pathogen interactions from a metabolic perspective: methods of investigation.

Caroline Demangel, Laura Surace.

Metabolism shapes immune homeostasis in health and disease. This review presents the range of methods that are currently available to investigate the dialog between metabolism and immunity at the systemic, tissue and cellular levels, particularly during infection.

DOI: https://doi.org/10.1016/j.micinf.2023.105267
Ecotoxicol Environ Saf. 2023 Nov 30. pii: S0147-6513(23)01271-X. [Epub ahead of print]269 115767

2-Deoxy-D-glucose ameliorates inflammation and fibrosis in a silicosis mouse model by inhibiting hypoxia-inducible factor-1α in alveolar macrophages.

Yuting Lu, Min Mu, Xiaotian RenChen, Wenyang Wang, Yingrui Zhu, Meiping Zhong, Yuerong Jiang, Xinrong Tao.

  Inhaling silica causes the occupational illness silicosis, which mostly results in the gradual fibrosis of lung tissue. Previous research has demonstrated that hypoxia-inducible factor-1α (HIF-1α) and glycolysis-related genes are up-regulated in silicosis. The role of 2-deoxy-D-glucose (2-DG) as an inhibitor of glycolysis in silicosis mouse models and its molecular mechanisms remain unclear. Therefore, we used 2-DG to observe its effect on pulmonary inflammation and fibrosis in a silicosis mouse model. Furthermore, in vitro cell experiments were conducted to explore the specific mechanisms of HIF-1α. Our study found that 2-DG down-regulated HIF-1α levels in alveolar macrophages induced by silica exposure and reduced the interleukin-1β (IL-1β) level in pulmonary inflammation. Additionally, 2-DG reduced silica-induced pulmonary fibrosis. From these findings, we hypothesize that 2-DG reduced glucose transporter 1 (GLUT1) expression by inhibiting glycolysis, which inhibits the expression of HIF-1α and ultimately reduces transcription of the inflammatory cytokine, IL-1β, thus alleviating lung damage. Therefore, we elucidated the important regulatory role of HIF-1α in an experimental silicosis model and the potential defense mechanisms of 2-DG. These results provide a possible effective strategy for 2-DG in the treatment of silicosis.

Keywords:  2-DG; Alveolar macrophages; HIF-1α; Inflammation; Silicosis

DOI:  https://doi.org/10.1016/j.ecoenv.2023.115767
Pharmacol Res. 2023 Nov 24. pii: S1043-6618(23)00372-9. [Epub ahead of print]198 107016

The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.

Xiaoyan Wu, Xin Yi, Boxin Zhao, Yuanxing Zhi, Ziwei Xu, Ying Cao, Xiong Cao, Jianxin Pang, Ken Kin Lam Yung, Shiqing Zhang, Shuwen Liu, Pingzheng Zhou.

  The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+ efflux for NLRP3 stimuli that require K+ efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice with Lrrc8a deficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases.

Keywords:  Cell volume regulation; Immunometabolism; Innate immunity; LRRC8; Macrophage activation; Sepsis

DOI:  https://doi.org/10.1016/j.phrs.2023.107016
Nat Metab. 2023 Nov 27.

Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.

David Ngai, Maaike Schilperoort, Ira Tabas.

The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.

DOI: https://doi.org/10.1038/s42255-023-00921-9
bioRxiv. 2023 Nov 15. pii: 2023.11.13.566832. [Epub ahead of print]

Pyruvate Oxidation Sustains B Cell Antigen-Specific Activation to Exacerbate MASH.

Fanta Barrow, Haiguang Wang, Gavin Fredrickson, Kira Florczak, Erin Ciske, Shalil Khanal, Preethy Parthiban, Huy Nguyen, Enrique Rios, Enis Kostallari, Xavier S Revelo.

B cells play a crucial role in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease that if persistent can lead to cirrhosis, liver failure, and cancer. Chronic inflammation and fibrosis are key features of MASH that determine disease progression and outcomes. Recent advances have revealed that pathogenic B cell-derived cytokines and antibodies promote the development of MASH. However, the mechanisms through which B cells promote fibrosis and the metabolic adaptations underlying their pathogenic responses remain unclear. Here, we report that a subset of mature B cells with heightened cytokine responses accumulate in the liver and promote inflammation in MASH. To meet the increased energetic demand of effector responses, B cells increase their ATP production via oxidative phosphorylation (OXPHOS) fueled by pyruvate oxidation in a B cell receptor (BCR)-specific manner. Blocking pyruvate oxidation completely abrogated the inflammatory capacity of MASH B cells. Accordingly, the restriction of the BCR led to MASH attenuation, including reductions in steatosis, hepatic inflammation, and fibrosis. Mechanistically, BCR restriction decreased B cell maturation, activation, and effector responses in the liver, accompanied by decreased T cell- and macrophage-mediated inflammation. Notably, attenuated liver fibrosis in BCR-restricted mice was associated with lower IgG production and decreased expression of Fc-gamma receptors on hepatic stellate cells. Together, these findings indicate a key role for B cell antigen-specific responses in promoting steatosis, inflammation, and fibrosis during MASH.

DOI: https://doi.org/10.1101/2023.11.13.566832
Endocrinology. 2023 Dec 01. pii: bqad181. [Epub ahead of print]

Dectin-2 Deficiency Promotes Pro-inflammatory Cytokine Release from Macrophages and Impairs Insulin Secretion.

Masamichi Fujita, Takashi Miyazawa, Keiichiro Uchida, Naohiro Uchida, Shojiro Haji, Seiichi Yano, Norifusa Iwahashi, Tomomi Hatayama, Shunsuke Katsuhara, Shintaro Nakamura, Yukina Takeichi, Maki Yokomoto-Umakoshi, Yasutaka Miyachi, Ryuichi Sakamoto, Yoichiro Iwakura, Yoshihiro Ogawa.

  Pancreatic islet inflammation plays a crucial role in the etiology of type 2 diabetes (T2D). Macrophages residing in pancreatic islets have emerged as key players in islet inflammation. Macrophages express a plethora of innate immune receptors that bind to environmental and metabolic cues and integrate these signals to trigger an inflammatory response that contributes to the development of islet inflammation. One such receptor, Dectin-2, has been identified within pancreatic islets; however, its role in glucose metabolism remains largely unknown. Here we demonstrated that mice lacking Dectin-2 exhibit local inflammation within islets, along with impaired insulin secretion and β-cell dysfunction. Our findings indicate that these effects are mediated by pro-inflammatory cytokines, such as IL-1α and IL-6, which are secreted by macrophages that have acquired an inflammatory phenotype because of the loss of Dectin-2. This study provides novel insights into the mechanisms underlying the role of Dectin-2 in the development of islet inflammation.

Keywords:  Dectin-2; glucose-stimulated insulin secretion; inflammatory cytokines; islet inflammation; macrophage

DOI:  https://doi.org/10.1210/endocr/bqad181
Cancer Lett. 2023 Nov 25. pii: S0304-3835(23)00462-7. [Epub ahead of print]581 216511

PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.

Shishuo Sun, Heng Xu, Wanxin Zhao, Qihong Li, Yifan Yuan, Guopeng Zhang, Shuyu Li, Bixi Wang, Wei Zhang, Xiaoge Gao, Junnian Zheng, Qing Zhang.

  Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit cancer immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.

Keywords:  Antitumor immunity; OA; PA; T cells; TME

DOI:  https://doi.org/10.1016/j.canlet.2023.216511
J Gastroenterol Hepatol. 2023 Nov 27.

Effect of triggering receptor expressed on myeloid cells 2-associated alterations on lipid metabolism in macrophages in the development of non-alcoholic fatty liver disease.

Pei-Xuan Ji, Yu-Xin Chen, Xi-Xi Ni, Qi Miao, Jing Hua.

  BACKGROUND AND AIM: Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in metabolic homeostasis and inflammatory response. Altered metabolic function in macrophages could modulate their activation and immune phenotype. The present study aimed to investigate the expression of TREM2 in non-alcoholic fatty liver disease (NAFLD) and to clarify the underlying mechanism of TREM2 on macrophages lipid metabolism and oxidative stress.METHODS: Hepatic TREM2 expression and its relationship with NAFLD progression were analyzed in patients with NAFLD and mice fed a high-fat diet. Lipid metabolism and oxidative stress were investigated in macrophages from NAFLD mice or stimulated with saturated fatty acids. Knockdown and overexpression of TREM2 were further explored.
RESULTS: Triggering receptor expressed on myeloid cells 2+ macrophages were increased along with NAFLD development, characterized by aggravated steatosis and liver damage in humans and mice. TREM2 expression was upregulated and lipid metabolism was changed in macrophages from NAFLD mice or metabolically activated by saturated fatty acid in vitro, as demonstrated by increased lipid uptake and catabolism, but reduced de novo synthesis of fatty acids (FAs). Regulation of TREM2 expression in lipid-laden macrophages reprogrammed lipid metabolism, especially the fatty acid oxidation capacity of mitochondria. TREM2 knockdown promoted oxidative stress by aggravating FAs deposition in mitochondria. Intervention of mitochondrial FAs transport in lipid-laden macrophages alleviated FA deposition and reactive oxygen species production induced by TREM2 knockdown.
CONCLUSIONS: Triggering receptor expressed on myeloid cells 2 expression was associated with the lipid metabolic profile and reactive oxygen species production in macrophages. High expression of TREM2 in macrophages may protect the liver from oxidative stress in NAFLD.

Keywords:  lipid metabolism; macrophages; non-alcoholic fatty liver disease; oxidative stress; triggering receptor expressed on myeloid cells 2

DOI:  https://doi.org/10.1111/jgh.16417
J Immunol. 2023 Dec 01. pii: ji2200835. [Epub ahead of print]

Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.

Maximilian Nickenig, Matthew S J Mangan, Hye Eun Lee, Konstantinos Symeonidis, Antonia Henne, Romina Kaiser, Eike Geißmar, Hendrikus Garritsen, Zeinab Abdullah, Karsten Hiller, Eicke Latz, Mario A Lauterbach.

The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.

DOI: https://doi.org/10.4049/jimmunol.2200835
bioRxiv. 2023 Nov 15. pii: 2023.11.13.566775. [Epub ahead of print]

Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment.

Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.

The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.

DOI: https://doi.org/10.1101/2023.11.13.566775
Front Immunol. 2023 ;14 1290191

Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection.

Kwang H Kim, Donghwan Park, Soo Young Cho, Yejin Cho, Buhyun Lee, Haengdueng Jeong, Yura Lee, Yourim Lee, Ki Taek Nam.

  Macrophages are highly heterogeneous immune cells with a role in maintaining tissue homeostasis, especially in activating the defense response to bacterial infection. Using flow cytometric and single-cell RNA-sequencing analyses of peritoneal cells, we here show that small peritoneal macrophage and immature macrophage populations are enriched in histamine-deficient (Hdc -/-) mice, characterized by a CD11bmiF4/80loCCR2+MHCIIhi and CD11bloF4/80miTHBS1+IL-1α+ phenotype, respectively. Molecular characterization revealed that immature macrophages represent an abnormally differentiated form of large peritoneal macrophages with strong inflammatory properties. Furthermore, deficiency in histamine signaling resulted in significant impairment of the phagocytic activity of peritoneal macrophage populations, conferring high susceptibility to bacterial infection. Collectively, this study reveals the importance of histamine signaling in macrophage differentiation at the molecular level to maintain tissue homeostasis, offering a potential therapeutic target for bacterial infection-mediated diseases.

Keywords:  bacterial infection; histamine; macrophage differentiation; peritoneal cells; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2023.1290191
Microbes Infect. 2023 Nov 28. pii: S1286-4579(23)00179-X. [Epub ahead of print] 105271

Butyrate induces oxidative burst mediated apoptosis via Glucose-6-Phosphate Dehydrogenase (G6PDH) in macrophages during mycobacterial infection.

Ankush Kumar Rana, Shakuntala Surendra Kumar Saraswati, Vandana Anang, Aayushi Singh, Aarti Singh, Chaitenya Verma, Krishnamurthy Natarajan.

  Microorganisms present in the gut modulate host defence responses against infections in order to maintain immune homeostasis. This host-microbe crosstalk is regulated by gut metabolites. Butyrate is one such small chain fatty acid produced by gut microbes upon fermentation that has the potential to influence immune responses. Here we investigated the role of butyrate in macrophages during mycobacterial infection. Results demonstrate that butyrate significantly suppresses the growth kinetics of mycobacteria in culture medium as well as inhibits mycobacterial survival inside macrophages. Interestingly, butyrate alters the pentose phosphate pathway by inducing higher expression of Glucose-6-Phosphate Dehydrogenase (G6PDH) resulting in a higher oxidative burst via decreased Sod-2 and increased Nox-2 (NADPH oxidase-2) expression. Butyrate-induced G6PDH also mediated a decrease in mitochondrial membrane potential. This in turn lead to an induction of apoptosis as measured by lower expression of the anti-apoptotic protein Bcl-2 and a higher release of Cytochrome C as a result of induction of apoptosis. These results indicate that butyrate alters the metabolic status of macrophages and induces protective immune responses against mycobacterial infection.

Keywords:  Apoptosis; Butyrate; G6PDH; M bovis BCG; ROS; Tuberculosis

DOI:  https://doi.org/10.1016/j.micinf.2023.105271
iScience. 2023 Nov 17. 26(11): 108279

Lactobacillus-derived indole-3-lactic acid ameliorates colitis in cesarean-born offspring via activation of aryl hydrocarbon receptor.

Yanan Xia, Chang Liu, Ruijia Li, Mengqi Zheng, Bingcheng Feng, Jiahui Gao, Xin Long, Lixiang Li, Shiyang Li, Xiuli Zuo, Yanqing Li.

  Cesarean section (CS) delivery is known to disrupt the transmission of maternal microbiota to offspring, leading to an increased risk of inflammatory bowel disease (IBD). However, the underlying mechanisms remain poorly characterized. Here, we demonstrate that CS birth renders mice susceptible to dextran sulfate sodium (DSS)-induced colitis and impairs group 3 innate lymphoid cell (ILC3) development. Additionally, CS induces a sustained decrease in Lactobacillus abundance, which subsequently contributes to the colitis progression and ILC3 deficiency. Supplementation with a probiotic strain, L. acidophilus, or its metabolite, indole-3-lactic acid (ILA), can attenuate intestinal inflammation and restore ILC3 frequency and interleukin (IL)-22 level in CS offspring. Mechanistically, we indicate that ILA activates ILC3 through the aryl hydrocarbon receptor (AhR) signaling. Overall, our findings uncover a detrimental role of CS-induced gut dysbiosis in the pathogenesis of colitis and suggest L. acidophilus and ILA as potential targets to re-establish intestinal homeostasis in CS offspring.

Keywords:  Biological sciences; Immunology; Microbiology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2023.108279
Front Immunol. 2023 ;14 1259434

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis.

Qiuhua Yang, Emily Huo, Yongfeng Cai, Zhidan Zhang, Charles Dong, John M Asara, Huidong Shi, Qingqing Wei.

  Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby's group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3 ΔMϕ ) and their wild type littermates (Pfkfb3 WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3 ΔMϕ mice compared to Pfkfb3 WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3 ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.

Keywords:  PFKFB3; glycolysis; inflammation; macrophage; renal fibrosis

DOI:  https://doi.org/10.3389/fimmu.2023.1259434
Shock. 2023 Nov 16.

Metformin mitigates sepsis-associated pulmonary fibrosis by promoting AMPK activation and inhibiting Hif-1α-induced aerobic glycolysis.

Han Zhong, Ri Tang, Jin-Hua Feng, Ya-Wen Peng, Qiao-Yi Xu, Yang Zhou, Zheng-Yu He, Shu-Ya Mei, Shun-Peng Xing.

ABSTRACT: Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis. However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α) induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide (LPS) increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. Additionally, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates pulmonary fibrosis associated with sepsis, which is caused by aerobic glycolysis, in mice. HIF-1α knockdown demonstrated similar protective effects in vivo. Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated pulmonary fibrosis.

DOI: https://doi.org/10.1097/SHK.0000000000002275
Front Immunol. 2023 ;14 1286696

ATP-dependent transporters: emerging players at the crossroads of immunity and metabolism.

Akshaya Balasubramanian, Mark S Sundrud.

  Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes - ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides - into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the ABCB1 locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.

Keywords:  ABC transporters; MDR1; P-glycoprotein; TCR signaling; metabolism; oxidative stress; reactive oxygen species; redox

DOI:  https://doi.org/10.3389/fimmu.2023.1286696
Clin Immunol. 2023 Nov 28. pii: S1521-6616(23)00619-8. [Epub ahead of print] 109855

Novel SLC5A6 mutations lead to B lymphocyte maturation defects with metabolic abnormality rescuable by biotin replenishment.

Chu-Han Hsieh, Ju Lee, Hsiang-Hsuan Sung, Ya-Fang Huang, Yu-Sian Ding, Chia-Yi Li, Chia-Liang Yen, Chao-Kai Hsu, Chun-Keung Yu, Hsin-Ying Hsieh, Michael Warren Hughes, Peng-Chieh Chen, Chi-Chang Shieh.

  We characterized a family diagnosed with immunodeficiency disease presenting with low immunoglobulin levels and skin dyskeratosis. Exome sequencing revealed compound heterozygous missense variants in SLC5A6, the gene encoding a cellular sodium-dependent multivitamin transporter (SMVT) responsible for transporting vitamins, including biotin (vitamin B7). We showed that the biotin deficiency was caused by the SLC5A6 variants resulting in defective B cell differentiation and antibody deficiency. Altered cellular metabolic profiles, including aberrant mitochondrial respiration and reliance on glycolysis, may underlie the failure in plasma cell maturation. Replenishment of biotin improved plasma cell maturation and recovered the antibody producing activity in the patient and in a CRISPR-Cas9 gene-edited mouse model bearing a patient-specific SLC5A6 variant. Our results demonstrate the critical role of metabolic reprogramming in the maturation of plasma cells and nominate SLC5A6 as a causative gene for immunodeficiency that may be treated by biotin replenishment.

Keywords:  B cell differentiation; Biotin; Immunometabolism; Primary immunodeficiency diseases; SLC5A6

DOI:  https://doi.org/10.1016/j.clim.2023.109855
Nat Commun. 2023 Nov 30. 14(1): 7889

The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.

Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh.

Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.

DOI: https://doi.org/10.1038/s41467-023-43635-y
bioRxiv. 2023 Nov 16. pii: 2023.11.14.567048. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sadie Johnson, Mary McGraw, Matthew M Grabowski, Tianyao Lu, Lutz Freytag, Vinod Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin D Lathia.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

DOI: https://doi.org/10.1101/2023.11.14.567048
Mater Today Bio. 2023 Dec;23 100832

SEMA4D/VEGF surface enhances endothelialization by diminished-glycolysis-mediated M2-like macrophage polarization.

Yuanyuan Cui, Xiaomei Jiang, Maozhu Yang, Yinglin Yuan, Zili Zhou, Xiang Gao, Guiqing Jia, Lvzhou Cao, Danni Li, Yanshuang Zhao, Xin Zhang, Gaoping Zhao.

  Cardiovascular disease remains the leading cause of death and morbidity worldwide. Inflammatory responses after percutaneous coronary intervention led to neoathrosclerosis and in-stent restenosis and thus increase the risk of adverse clinical outcomes. In this work, a metabolism reshaped surface is engineered, which combines the decreased glycolysis promoting, M2-like macrophage polarization, and rapid endothelialization property. Anionic heparin plays as a linker and mediates cationic SEMA4D and VEGF to graft electronically onto PLL surfaces. The system composed by anticoagulant heparin, immunoregulatory SEMA4D and angiogenic VEGF endows the scaffold with significant inhibition of platelets, fibrinogen and anti-thrombogenic properties, also noteworthy immunometabolism reprogram, anti-inflammation M2-like polarization and finally leading to rapid endothelializaiton performances. Our research indicates that the immunometabolism method can accurately reflect the immune state of modified surfaces. It is envisioned immunometabolism study will open an avenue to the surface engineering of vascular implants for better clinical outcomes.

Keywords:  Endothelialization; Immunometabolism; M2-like macrophage phenotype; Semaphorin 4D (SEMA4D); Vascular endothelial growth factor (VEGF)

DOI:  https://doi.org/10.1016/j.mtbio.2023.100832
Redox Biol. 2023 Nov 23. pii: S2213-2317(23)00369-5. [Epub ahead of print]68 102968

Restoring the infected powerhouse: Mitochondrial quality control in sepsis.

F M Lira Chavez, L P Gartzke, F E van Beuningen, S E Wink, R H Henning, G Krenning, H R Bouma.

  Sepsis is a dysregulated host response to an infection, characterized by organ failure. The pathophysiology is complex and incompletely understood, but mitochondria appear to play a key role in the cascade of events that culminate in multiple organ failure and potentially death. In shaping immune responses, mitochondria fulfil dual roles: they not only supply energy and metabolic intermediates crucial for immune cell activation and function but also influence inflammatory and cell death pathways. Importantly, mitochondrial dysfunction has a dual impact, compromising both immune system efficiency and the metabolic stability of end organs. Dysfunctional mitochondria contribute to the development of a hyperinflammatory state and loss of cellular homeostasis, resulting in poor clinical outcomes. Already in early sepsis, signs of mitochondrial dysfunction are apparent and consequently, strategies to optimize mitochondrial function in sepsis should not only prevent the occurrence of mitochondrial dysfunction, but also cover the repair of the sustained mitochondrial damage. Here, we discuss mitochondrial quality control (mtQC) in the pathogenesis of sepsis and exemplify how mtQC could serve as therapeutic target to overcome mitochondrial dysfunction. Hence, replacing or repairing dysfunctional mitochondria may contribute to the recovery of organ function in sepsis. Mitochondrial biogenesis is a process that results in the formation of new mitochondria and is critical for maintaining a pool of healthy mitochondria. However, exacerbated biogenesis during early sepsis can result in accumulation of structurally aberrant mitochondria that fail to restore bioenergetics, produce excess reactive oxygen species (ROS) and exacerbate the disease course. Conversely, enhancing mitophagy can protect against organ damage by limiting the release of mitochondrial-derived damage-associated molecules (DAMPs). Furthermore, promoting mitophagy may facilitate the growth of healthy mitochondria by blocking the replication of damaged mitochondria and allow for post sepsis organ recovery through enabling mitophagy-coupled biogenesis. The remaining healthy mitochondria may provide an undamaged scaffold to reproduce functional mitochondria. However, the kinetics of mtQC in sepsis, specifically mitophagy, and the optimal timing for intervention remain poorly understood. This review emphasizes the importance of integrating mitophagy induction with mtQC mechanisms to prevent undesired effects associated with solely the induction of mitochondrial biogenesis.

Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Sepsis

DOI:  https://doi.org/10.1016/j.redox.2023.102968
Front Immunol. 2023 ;14 1271098

Impact of norepinephrine on immunity and oxidative metabolism in sepsis.

Joby Thoppil, Prayag Mehta, Brett Bartels, Drashya Sharma, J David Farrar.

  Sepsis is a major health problem in the United States (US), constituting a leading contributor to mortality among critically ill patients. Despite advances in treatment the underlying pathophysiology of sepsis remains elusive. Reactive oxygen species (ROS) have a significant role in antimicrobial host defense and inflammation and its dysregulation leads to maladaptive responses because of excessive inflammation. There is growing evidence for crosstalk between the central nervous system and the immune system in response to infection. The hypothalamic-pituitary and adrenal axis and the sympathetic nervous system are the two major pathways that mediate this interaction. Epinephrine (Epi) and norepinephrine (NE), respectively are the effectors of these interactions. Upon stimulation, NE is released from sympathetic nerve terminals locally within lymphoid organs and activate adrenoreceptors expressed on immune cells. Similarly, epinephrine secreted from the adrenal gland which is released systemically also exerts influence on immune cells. However, understanding the specific impact of neuroimmunity is still in its infancy. In this review, we focus on the sympathetic nervous system, specifically the role the neurotransmitter norepinephrine has on immune cells. Norepinephrine has been shown to modulate immune cell responses leading to increased anti-inflammatory and blunting of pro-inflammatory effects. Furthermore, there is evidence to suggest that norepinephrine is involved in regulating oxidative metabolism in immune cells. This review attempts to summarize the known effects of norepinephrine on immune cell response and oxidative metabolism in response to infection.

Keywords:  immune cells; norepinephrine; oxidative metabolism; sepsis; sympathetic nervous system

DOI:  https://doi.org/10.3389/fimmu.2023.1271098
J Immunol. 2023 Nov 29. pii: ji2300090. [Epub ahead of print]

The Microbial Tryptophan Metabolite Contributes to the Remission of Salmonella typhimurium Infection in Mice.

Yingying Li, Junqi Li, Dan Jia, Shandian Gao, Yanan Guo, Junlong Liu, Jinming Wang, Guiquan Guan, Jianxun Luo, Hong Yin, Sa Xiao, Youquan Li.

Salmonella enterica serovar Typhimurium (S. Tm) causes severe foodborne diseases. Interestingly, gut microbial tryptophan (Trp) metabolism plays a pivotal role in such infections by a yet unknown mechanism. This study aimed to explore the impact of Trp metabolism on S. Tm infection and the possible mechanisms involved. S. Tm-infected C57BL6/J mice were used to demonstrate the therapeutic benefits of the Bacillus velezensis JT3-1 (B. velezensis/JT3-1) strain or its cell-free supernatant in enhancing Trp metabolism. Targeted Trp metabolomic analyses indicated the predominance of indole-3-lactic acid (ILA), an indole derivative and ligand for aryl hydrocarbon receptor (AHR). Based on the 16S amplicon sequencing and correlation analysis of metabolites, we found that B. velezensis supported the relative abundance of Lactobacillus and Ligilactobacillus in mouse gut and showed positive correlations with ILA levels. Moreover, AHR and its downstream genes (especially IL-22) significantly increased in mouse colons after B. velezensis or cell-free supernatant treatment, suggesting the importance of AHR pathway activation. In addition, ILA was found to stimulate primary mouse macrophages to secrete IL-22, which was antagonized by CH-223191. Furthermore, ILA could protect mice from S. Tm infection by increasing IL-22 in Ahr+/- mice, but not in Ahr-/- mice. Finally, Trp-rich feeding showed amelioration of S. Tm infection in mice, and the effect depended on gut microbiota. Taken together, these results suggest that B. velezensis-associated ILA contributes to protecting mice against S. Tm infection by activating the AHR/IL-22 pathway. This study provides insights into the involvement of microbiota-derived Trp catabolites in protecting against Salmonella infection.

DOI: https://doi.org/10.4049/jimmunol.2300090
J Inflamm Res. 2023 ;16 5261-5272

Disturbance of Adaptive Immunity System Was Accompanied by a Decrease in Plasma Short-Chain Fatty Acid for Patients Hospitalized During SARS-CoV-2 Infection After COVID-19 Vaccination.

Zhaojun Liang, Nan Wang, Chunxue Fan, Lili Shang, Yaping Zhang, Chong Gao, Jing Luo.

  Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to disorders of immune function and a decrease in the diversity of intestinal flora. We aimed to explore the changes of circulating immune cell subsets and the plasma level of intestinal short-chain fatty acids (SCFAs) in patients with Coronavirus disease 2019 (COVID-19), further understanding the pathogenesis of COVID-19.Methods: The study included 83 newly diagnosed COVID-19 patients and 39 non-COVID-19 controls. All have completed a full course of vaccination against SARS-CoV-2. The levels of peripheral lymphocyte subsets and plasma cytokines were detected by flow cytometry. Targeted metabolomics was used to explore the level of SCFAs in plasma.
Results: Compared with the non-COVID-19 group, COVID-19 patients showed a decrease in CD19+B cells, CD4+T cells, CD8+T cells, NK cells, CD4+CD8+T cells and CD4-CD8-T cells (all p<0.001) and concomitantly an increase in sIL-2R, IL-6 and IL-10 (all p<0.005). These alterations were more pronounced in those critical patients. In addition, COVID-19 patients had lower levels of propanoic acid (PA), butyric acid (BA), isobutyric acid (IBA) and isohexanoic acid (ICA) (all p<0.01). Among them, the level of ICA is positively correlated with the absolute number of immune cells.
Conclusion: Our study suggests the immune cell subsets in COVID-19 patients who had completed vaccination were still severely disturbed and concomitantly lower SCFAs, especially in severe patients with poor prognosis. Lower levels of plasma SCFAs may contribute to lymphopenia in COVID-19. The potential relationship between plasma SCFAs and immune cell reduction provides a new direction for the treatment of COVID-19.

Keywords:  adaptive immunity; coronavirus disease 2019; severe acute respiratory syndrome coronavirus 2; short-chain fatty acids

DOI:  https://doi.org/10.2147/JIR.S434860
Exp Mol Med. 2023 Dec 01.

Disruption of cholesterol homeostasis triggers periodontal inflammation and alveolar bone loss.

Thanh-Tam Tran, Gyuseok Lee, Yun Hyun Huh, Ki-Ho Chung, Sun Young Lee, Ka Hyon Park, Seung Hee Kwon, Min-Suk Kook, Jang-Soo Chun, Jeong-Tae Koh, Je-Hwang Ryu.

Oral diseases exhibit a significant association with metabolic syndrome, including dyslipidemia. However, direct evidence supporting this relationship is lacking, and the involvement of cholesterol metabolism in the pathogenesis of periodontitis (PD) has yet to be determined. In this study, we showed that high cholesterol caused periodontal inflammation in mice. Cholesterol homeostasis in human gingival fibroblasts was disrupted by enhanced uptake through C-X-C motif chemokine ligand 16 (CXCL16), upregulation of cholesterol hydroxylase (CH25H), and the production of 25-hydroxycholesterol (an oxysterol metabolite of CH25H). Retinoid-related orphan receptor α (RORα) mediated the transcriptional upregulation of inflammatory mediators; consequently, PD pathogenesis mechanisms, including alveolar bone loss, were stimulated. Our collective data provided direct evidence that hyperlipidemia is a risk factor for PD and supported that inhibition of the CXCL16-CH25H-RORα axis is a potential treatment mechanism for PD as a systemic disorder manifestation.

DOI: https://doi.org/10.1038/s12276-023-01122-w
Front Microbiol. 2023 ;14 1270762

Metabolomic profiling of Marek's disease virus infection in host cell based on untargeted LC-MS.

Qingsen Wang, Bin Shi, Guifu Yang, Xueying Zhu, Hongxia Shao, Kun Qian, Jianqiang Ye, Aijian Qin.

  Marek's disease (MD) caused by Marek's disease virus (MDV), poses a serious threat to the poultry industry by inducing neurological disease and malignant lymphoma in infected chickens. However, the underlying mechanisms how MDV disrupts host cells and causes damage still remain elusive. Recently, the application of metabolomics has shown great potential for uncovering the complex mechanisms during virus-host interactions. In this study, chicken embryo fibroblasts (CEFs) infected with MDV were subjected to ultrahigh-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS) and multivariate statistical analysis. The results showed that 261 metabolites were significantly altered upon MDV infection, with most changes occurring in amino acid metabolism, energy metabolism, nucleotide metabolism, and lipid metabolism. Notably, MDV infection induces an up-regulation of amino acids in host cells during the early stages of infection to provide the energy and intermediary metabolites necessary for efficient multiplication of its own replication. Taken together, these data not only hold promise in identifying the biochemical molecules utilized by MDV replication in host cells, but also provides a new insight into understanding MDV-host interactions.

Keywords:  CEFs; LC-MS; Marek’s disease virus; amino acid; metabolites; the TCA cycle

DOI:  https://doi.org/10.3389/fmicb.2023.1270762