bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024–04–21
twenty-six papers selected by
Dylan Ryan, University of Cambridge
  1. Diet switch pre-vaccination improves immune response and metabolic status in formerly obese mice.
  2. Iron Is Critical for Mucosal-Associated Invariant T Cell Metabolism and Effector Functions.
  3. Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
  4. Highlight of 2023: The metabolic symphony - orchestrating T-cell immunity.
  5. Excitatory amino acid transporter supports inflammatory macrophage responses.
  6. Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism.
  7. Metabolic programming of organ-specific natural killer cell responses.
  8. Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis.
  9. LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.
  10. The essential link: How STAT3 connects tumor metabolism to immunity.
  11. SIRT3 negatively regulates TFH cell differentiation in cancer.
  12. AMPK restricts HHV-6A replication by inhibiting glycolysis and mTOR signaling.
  13. Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.
  14. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19.
  15. 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.
  16. Oxidized low-density lipoprotein changes the inflammatory status and metabolomics profiles in human and mouse macrophages and microglia.
  17. Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.
  18. Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism.
  19. Short-chain fatty acid-producing bacterial strains attenuate experimental ulcerative colitis by promoting M2 macrophage polarization via JAK/STAT3/FOXO3 axis inactivation.
  20. Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.
  21. Sweet regulation - The emerging immunoregulatory roles of hexoses.
  22. Progression of herpesvirus infection remodels mitochondrial organization and metabolism.
  23. Impacts of liver macrophages, gut microbiota, and bile acid metabolism on the differences in iHFC diet-induced MASH progression between TSNO and TSOD mice.
  24. Dietary fiber guar gum-induced shift in gut microbiota metabolism and intestinal immune activity enhances susceptibility to colonic inflammation.
  25. VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis.
  26. Redox regulation of macrophages.
  1. Nat Microbiol. 2024 Apr 18.
    Diet switch pre-vaccination improves immune response and metabolic status in formerly obese mice.
    Rebekah Honce, Ana Vazquez-Pagan, Brandi Livingston, Alexandra H Mandarano, Benjamin A Wilander, Sean Cherry, Virginia Hargest, Bridgett Sharp, Pamela H Brigleb, Ericka Kirkpatrick Roubidoux, Lee-Ann Van de Velde, R Chris Skinner, Maureen A McGargill, Paul G Thomas, Stacey Schultz-Cherry.
      Metabolic disease is epidemiologically linked to severe complications upon influenza virus infection, thus vaccination is a priority in this high-risk population. Yet, vaccine responses are less effective in these same hosts. Here we examined how the timing of diet switching from a high-fat diet to a control diet affected influenza vaccine efficacy in diet-induced obese mice. Our results demonstrate that the systemic meta-inflammation generated by high-fat diet exposure limited T cell maturation to the memory compartment at the time of vaccination, impacting the recall of effector memory T cells upon viral challenge. This was not improved with a diet switch post-vaccination. However, the metabolic dysfunction of T cells was reversed if weight loss occurred 4 weeks before vaccination, restoring a functional recall response. This corresponded with changes in the systemic obesity-related biomarkers leptin and adiponectin, highlighting the systemic and specific effects of diet on influenza vaccine immunogenicity.
    DOI:  https://doi.org/10.1038/s41564-024-01677-y
  2. J Immunol. 2024 Apr 15. pii: ji2300649. [Epub ahead of print]
    Iron Is Critical for Mucosal-Associated Invariant T Cell Metabolism and Effector Functions.
    Eimear K Ryan, Christy Clutter, Conor De Barra, Benjamin J Jenkins, Simon O'Shaughnessy, Odhrán K Ryan, Chloe McKenna, Helen M Heneghan, Fiona Walsh, David K Finlay, Linda V Sinclair, Nicholas Jones, Daniel T Leung, Donal O'Shea, Andrew E Hogan.
      Mucosal-Associated Invariant T (MAIT) cells are a population of innate T cells that play a critical role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells can rapidly respond via both TCR-dependent and -independent mechanisms, resulting in robust cytokine production. The metabolic and nutritional requirements for optimal MAIT cell effector responses are still emerging. Iron is an important micronutrient and is essential for cellular fitness, in particular cellular metabolism. Iron is also critical for many pathogenic microbes, including those that activate MAIT cells. However, iron has not been investigated with respect to MAIT cell metabolic or functional responses. In this study, we show that human MAIT cells require exogenous iron, transported via CD71 for optimal metabolic activity in MAIT cells, including their production of ATP. We demonstrate that restricting iron availability by either chelating environmental iron or blocking CD71 on MAIT cells results in impaired cytokine production and proliferation. These data collectively highlight the importance of a CD71-iron axis for human MAIT cell metabolism and functionality, an axis that may have implications in conditions where iron availability is limited.
    DOI:  https://doi.org/10.4049/jimmunol.2300649
  3. Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2318420121
    Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
    Ajay Kumar, Chenxian Ye, Afia Nkansah, Thomas Decoville, Garrett M Fogo, Peter Sajjakulnukit, Mack B Reynolds, Li Zhang, Osbourne Quaye, Young-Ah Seo, Thomas H Sanderson, Costas A Lyssiotis, Cheong-Hee Chang.
      In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.
    Keywords:  heme; iron; mitochondria; tonic signaling
    DOI:  https://doi.org/10.1073/pnas.2318420121
  4. Immunol Cell Biol. 2024 Apr 17.
    Highlight of 2023: The metabolic symphony - orchestrating T-cell immunity.
    Lee M Booty.
      The significance of metabolites in orchestrating immune cells is now recognized to be on par with other key immune modulators, such as cytokines or chemokines. Seminal discoveries have now been built upon with discoveries that have acted to take the discipline to new heights, particularly in T-cell immunity. This accelerated progress has uncovered a plethora of opportunities for pharmacological intervention, with the aim of harnessing immunometabolism for refined immune modulation across several pathologies. This Research Highlight focuses on the latest breakthroughs during 2023 from the preceding year that provide mechanistic insight, as well as viable translational opportunities, in the field of T-cell immunometabolism.
    Keywords:  T cells; immunity; immunometabolism; metabolites
    DOI:  https://doi.org/10.1111/imcb.12750
  5. Sci Bull (Beijing). 2024 Mar 29. pii: S2095-9273(24)00211-1. [Epub ahead of print]
    Excitatory amino acid transporter supports inflammatory macrophage responses.
    Zhending Gan, Yan Guo, Muyang Zhao, Yuyi Ye, Yuexia Liao, Bingnan Liu, Jie Yin, Xihong Zhou, Yuqi Yan, Yulong Yin, Wenkai Ren.
      Excitatory amino acid transporters (EAATs) are responsible for excitatory amino acid transportation and are associated with auto-immune diseases in the central nervous system and peripheral tissues. However, the subcellular location and function of EAAT2 in macrophages are still obscure. In this study, we demonstrated that LPS stimulation increases expression of EAAT2 (coded by Slc1a2) via NF-κB signaling. EAAT2 is necessary for inflammatory macrophage polarization through sustaining mTORC1 activation. Mechanistically, lysosomal EAAT2 mediates lysosomal glutamate and aspartate efflux to maintain V-ATPase activation, which sustains macropinocytosis and mTORC1. We also found that mice with myeloid depletion of Slc1a2 show alleviated inflammatory responses in LPS-induced systemic inflammation and high-fat diet induced obesity. Notably, patients with type II diabetes (T2D) have a higher level of expression of lysosomal EAAT2 and activation of mTORC1 in blood macrophages. Taken together, our study links the subcellular location of amino acid transporters with the fate decision of immune cells, which provides potential therapeutic targets for the treatment of inflammatory diseases.
    Keywords:  Aspartate; Excitatory amino acid transporter; Glutamate; Macrophages; mTORC1
    DOI:  https://doi.org/10.1016/j.scib.2024.03.055
  6. Life Sci Alliance. 2024 Jul;pii: e202402609. [Epub ahead of print]7(7):
    Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism.
    Francesca Sciarretta, Fabio Zaccaria, Andrea Ninni, Veronica Ceci, Riccardo Turchi, Savina Apolloni, Martina Milani, Ilaria Della Valle, Marta Tiberi, Valerio Chiurchiù, Nadia D'Ambrosi, Silvia Pedretti, Nico Mitro, Cinzia Volontè, Susanna Amadio, Katia Aquilano, Daniele Lettieri-Barbato.
      Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.
    DOI:  https://doi.org/10.26508/lsa.202402609
  7. Immunol Rev. 2024 Apr 17.
    Metabolic programming of organ-specific natural killer cell responses.
    Rebecca B Delconte, Joseph C Sun.
      Cells of the mammalian innate immune system have evolved to protect the host from various environmental or internal insults and injuries which perturb the homeostatic state of the organism. Among the lymphocytes of the innate immune system are natural killer (NK) cells, which circulate and survey host tissues for signs of stress, including infection or transformation. NK cells rapidly eliminate damaged cells in the blood or within tissues through secretion of cytolytic machinery and production of proinflammatory cytokines. To perform these effector functions while traversing between the blood and tissues, patrolling NK cells require sufficient fuel to meet their energetic demands. Here, we highlight the ability of NK cells to metabolically adapt across tissues, during times of nutrient deprivation and within tumor microenvironments. Whether at steady state, or during viral infection and cancer, NK cells readily shift their nutrient uptake and usage in order to maintain metabolism, survival, and function.
    Keywords:  NK cells; cancer; immunity; immunometabolism
    DOI:  https://doi.org/10.1111/imr.13333
  8. Clin Exp Immunol. 2024 Apr 16. pii: uxae032. [Epub ahead of print]
    Dysregulated Lipid Metabolism Networks Modulate T-cell Function in People with Relapsing Remitting Multiple Sclerosis.
    Lucia Martin-Gutierrez, Kirsty E Waddington, Annalisa Maggio, Leda Coelewij, Alexandra Oppong, Nina Yang, Marsilio Adriani, Petra Nytrova, Rachel Farrell, Inés Pineda-Torra, Elizabeth C Jury.
      Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4+ T cells are pathogenic in RRMS, and defective T cell function could be mediated in part by liver X receptors (LXRs) - nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4+ T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4+ T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalised membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4+ T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
    Keywords:  CD4+ T cells; Lipid metabolism; Lipid rafts; Liver X Receptor; Multiple Sclerosis
    DOI:  https://doi.org/10.1093/cei/uxae032
  9. Cell Rep. 2024 Apr 15. pii: S2211-1247(24)00430-3. [Epub ahead of print] 114102
    LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.
    Ryo Terao, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Keitaro Hase, Shinobu Yamaguchi, Daniel Du, Brian S Sohn, Yo Sasaki, Mitsukuni Yoshida, Rajendra S Apte.
      Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.
    Keywords:  CD38; CP: Immunology; CP: Metabolism; NAD(+); NMN; age-related macular degeneration; cellular senescence; cholesterol efflux; neurodegeneration; nicotinamide adenine dinucleotide; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1016/j.celrep.2024.114102
  10. Biochim Biophys Acta Gene Regul Mech. 2024 Apr 16. pii: S1874-9399(24)00024-5. [Epub ahead of print] 195028
    The essential link: How STAT3 connects tumor metabolism to immunity.
    Shu Zhong, Jingjing Tong.
      Immunotherapy is a promising and long-lasting tumor treatment method, but it is challenged by the complex metabolism of tumors. To optimize immunotherapy, it is essential to further investigate the key proteins that regulate tumor metabolism and immune response. STAT3 plays a crucial role in regulating tumor dynamic metabolism and affecting immune cell function by responding to various cytokines and growth factors, which can be used as a potential target for immunotherapy. This review focuses on the crosstalk between STAT3 and tumor metabolism (including glucose, lipid, and amino acid metabolism) and its impact on the differentiation and function of immune cells such as T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), and reveals potential treatment strategies.
    Keywords:  Immune cell; Immunotherapy; Metabolism; STAT3; Tumor
    DOI:  https://doi.org/10.1016/j.bbagrm.2024.195028
  11. Cancer Immunol Res. 2024 Apr 17.
    SIRT3 negatively regulates TFH cell differentiation in cancer.
    Yueru Hou, Yejin Cao, Ying He, Lin Dong, Longhao Zhao, Yingjie Dong, Ruiying Niu, Yujing Bi, Guangwei Liu.
      Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors, but the mechanisms underlying TFH cell differentiation remain unclear. Here, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH cell differentiation and GC formation during tumor and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH cell differentiation and GC reactions during tumor and virus infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH cell differentiation. Blocking NAD+ synthesis-glycolysis signaling or recovering OXPHOS activities reversed the TFH cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and HIF1α signaling axis was found to be responsible for TFH cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl-6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and a mTOR-HIF1α-Bcl-6 pathway to reprogram TFH cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0786
  12. Virology. 2024 Apr 09. pii: S0042-6822(24)00101-6. [Epub ahead of print]595 110080
    AMPK restricts HHV-6A replication by inhibiting glycolysis and mTOR signaling.
    Xiaodi Yang, Siyu Tian, Zhujiang Min, Emanuela Garbarino, Jingjing Ma, Junli Jia, Huamin Tang, Lingyun Li.
      AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. In this study, we investigated the role of AMPK in response to human herpesvirus 6A (HHV-6A) infection. We show that HHV-6A infection significantly downregulates the active phosphorylated state of AMPK in infected T cells. Pharmacological activation of AMPK highly attenuated HHV-6A propagation. Mechanistically, we found that the activation of AMPK by AICAR blocked HHV-6-induced glycolysis by inhibiting glucose metabolism and lactate secretion, as well as decreasing expressions of key glucose transporters and glycolytic enzymes. In addition, mTOR signaling has been inactivated in HHV-6A infected T cells by AICAR treatment. We also showed that HHV-6A infection of human umbilical cord blood mononuclear cells (CBMCs) reduced AMPK activity whereas the activation of AMPK by metformin drastically reduced HHV-6A DNA replication and virions production. Taken together, this study demonstrates that AMPK is a promising antiviral therapeutic target against HHV-6A infection.
    Keywords:  AMPK; Glycolysis; HHV-6A; Virus replication; mTOR signaling
    DOI:  https://doi.org/10.1016/j.virol.2024.110080
  13. Adv Healthc Mater. 2024 Apr 16. e2400770
    Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.
    Xiaopei Wu, Yuhao Xia, Honglian Dai, Chuhang Hong, Yanan Zhao, Wenying Wei, Dian Zheng.
      Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, we fabricated a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis. Mechanistically, only outside M1 macrophages were accumulated high concentrations of citrate, in contrast, M2 macrophages consumed massive citrate. Therefore, citrate-functionalized scaffolds exerted more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate could block glycolysis related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. Our studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis. This article is protected by copyright. All rights reserved.
    Keywords:  citrate; glycolysis; macrophage polarization; metabolic control; osteoporotic bone regeneration; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/adhm.202400770
  14. Pharmacol Res. 2024 Apr 11. pii: S1043-6618(24)00114-2. [Epub ahead of print] 107170
    SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19.
    Joseph W Guarnieri, Jeffrey A Haltom, Yentli E Soto Albrecht, Timothy Lie, Arnold Z Olali, Gabrielle A Widjaja, Sujata S Ranshing, Alessia Angelin, Deborah Murdock, Douglas C Wallace.
      To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.
    Keywords:  Mitochondria; OXPHOS; SARS-CoV-2; epigenome; gene regulation; inhibitors; metabolism
    DOI:  https://doi.org/10.1016/j.phrs.2024.107170
  15. Immunity. 2024 Apr 12. pii: S1074-7613(24)00142-0. [Epub ahead of print]
    25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.
    Jun Xiao, Shuang Wang, Longlong Chen, Xinyu Ding, Yuanhao Dang, Mingshun Han, Yuxiao Zheng, Huan Shen, Sifan Wu, Mingchang Wang, Dan Yang, Na Li, Chen Dong, Miao Hu, Chen Su, Weiyun Li, Lijian Hui, Youqiong Ye, Huiru Tang, Bin Wei, Hongyan Wang.
      Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.
    Keywords:  25-hydroxycholesterol; AMPK; CH25H; M2-like macrophage; STAT6; cholesterol matabolism; oxysterol; tumor immunotherapy; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.021
  16. Heliyon. 2024 Apr 15. 10(7): e28806
    Oxidized low-density lipoprotein changes the inflammatory status and metabolomics profiles in human and mouse macrophages and microglia.
    Yaru Sun, Jia-Jian Liang, Jianming Xu, Kewen Zhou, Changzhen Fu, Shao-Lang Chen, Rucui Yang, Tsz Kin Ng, Qingping Liu, Mingzhi Zhang.
      The conjunctiva of primary open angle glaucoma patients showed high level of oxidized low-density lipoprotein (ox-LDL), which is associated with the inflammatory response. Microglia and macrophages are the immune cells involved in retinal ganglion cell survival regulation; yet, their roles of the ox-LDL-induced inflammation in glaucoma remain elusive. Here we aimed to investigate the lipid uptake, inflammatory cytokine expression, and metabolomics profiles of human and murine-derived microglial and macrophage cell lines treated with ox-LDL. Under the same ox-LDL concentration, macrophages exhibited higher lipid uptake and expression of pro-inflammatory cytokines as compared to microglia. The ox-LDL increased the levels of fatty acid metabolites in macrophages and sphingomyelin metabolites in microglia. In summary, this study revealed the heterogeneity in the inflammatory capacity and metabolic profiles of macrophages and microglia under the stimulation of ox-LDL.
    Keywords:  Inflammatory response; Macrophages; Metabolites; Microglia; Oxidized low-density lipoprotein
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e28806
  17. Sci Immunol. 2024 Apr 19. 9(94): eadg8817
    Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.
    Sicong Ma, Roger Sandhoff, Xiu Luo, Fuwei Shang, Qiaozhen Shi, Zhaolong Li, Jingxia Wu, Yanan Ming, Frank Schwarz, Alaa Madi, Nina Weisshaar, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora Ten Bosch, Zhe Li, Gernot Poschet, Hans-Reimer Rodewald, Nina Papavasiliou, Xi Wang, Pu Gao, Guoliang Cui.
      CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adg8817
  18. J Pineal Res. 2024 Apr;76(3): e12954
    Gut microbially produced tryptophan metabolite melatonin ameliorates osteoporosis via modulating SCFA and TMAO metabolism.
    Yueqi Chen, Chuan Yang, Zihan Deng, Tingwen Xiang, Qingrong Ni, Jianzhong Xu, Dong Sun, Fei Luo.
      Osteoporosis (OP) is a severe global health issue that has significant implications for productivity and human lifespan. Gut microbiota dysbiosis has been demonstrated to be closely associated with OP progression. Melatonin (MLT) is an important endogenous hormone that modulates bone metabolism, maintains bone homeostasis, and improves OP progression. Multiple studies indicated that MLT participates in the regulation of intestinal microbiota and gut barrier function. However, the promising effects of gut microbiota-derived MLT in OP remain unclear. Here, we found that OP resulted in intestinal tryptophan disorder and decreased the production of gut microbiota-derived MLT, while administration with MLT could mitigate OP-related clinical symptoms and reverse gut microbiota dysbiosis, including the diversity of intestinal microbiota, the relative abundance of many probiotics such as Allobaculum and Parasutterella, and metabolic function of intestinal flora such as amino acid metabolism, nucleotide metabolism, and energy metabolism. Notably, MLT significantly increased the production of short-chain fatty acids and decreased trimethylamine N-oxide-related metabolites. Importantly, MLT could modulate the dynamic balance of M1/M2 macrophages, reduce the serum levels of pro-inflammatory cytokines, and restore gut-barrier function. Taken together, our results highlighted the important roles of gut microbially derived MLT in OP progression via the "gut-bone" axis associated with SCFA metabolism, which may provide novel insight into the development of MLT as a promising drug for treating OP.
    Keywords:  M1/M2 macrophages; gut microbiota; melatonin (MLT); osteoporosis (OP); tryptophan metabolism
    DOI:  https://doi.org/10.1111/jpi.12954
  19. J Transl Med. 2024 Apr 18. 22(1): 369
    Short-chain fatty acid-producing bacterial strains attenuate experimental ulcerative colitis by promoting M2 macrophage polarization via JAK/STAT3/FOXO3 axis inactivation.
    Hailan Zhao, Youlian Zhou, Jing Xu, Yong Zhang, Hong Wang, Chong Zhao, Hongli Huang, Jing Yang, Chen Huang, Yingfei Li, Lisheng Wang, Yuqiang Nie.
       BACKGROUND: Patients with inflammatory bowel disease (IBD), dysbiosis, and immunosuppression who receive fecal microbiota transplantation (FMT) from healthy donors are at an increased risk of developing bacteremia. This study investigates the efficacy of a mixture of seven short-chain fatty acid (SCFA)-producing bacterial strains (7-mix), the resulting culture supernatant mixture (mix-sup), and FMT for treating experimental ulcerative colitis (UC) and evaluates underlying mechanisms.
    METHODS: Utilizing culturomics, we isolated and cultured SCFA-producing bacteria from the stool of healthy donors. We used a mouse model of acute UC induced by dextran sulfate sodium (DSS) to assess the effects of 7-mix, mix-sup, and FMT on intestinal inflammation and barrier function, microbial abundance and diversity, and gut macrophage polarization by flow cytometry, immunohistochemistry, 16S rRNA gene sequencing, and transwell assays.
    RESULTS: The abundance of several SCFA-producing bacterial taxa decreased in patients with UC. Seven-mix and mix-sup suppressed the inflammatory response and enhanced intestinal mucosal barrier function in the mouse model of UC to an extent similar to or superior to that of FMT. Moreover, 7-mix and mix-sup increased the abundance of SCFA-producing bacteria and SCFA concentrations in colitic mice. The effects of these interventions on the inflammatory response and gut barrier function were mediated by JAK/STAT3/FOXO3 axis inactivation in macrophages by inducing M2 macrophage polarization in vivo and in vitro.
    CONCLUSIONS: Our approach provides new opportunities to rationally harness live gut probiotic strains and metabolites to reduce intestinal inflammation, restore gut microbial composition, and expedite the development of safe and effective treatments for IBD.
    Keywords:  Bacterial mixture; Colitis; Macrophage polarization; Short-chain fatty acids
    DOI:  https://doi.org/10.1186/s12967-024-05122-w
  20. Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00422-4. [Epub ahead of print]43(4): 114094
    Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.
    Yongxiang Liu, Zifeng Wang, Huan Jin, Lei Cui, Bitao Huo, Chunyuan Xie, Jiahui Li, Honglu Ding, Huanling Zhang, Wenjing Xiong, Mengyun Li, Hongxia Zhang, Hui Guo, Chunwei Li, Tiantian Wang, Xiaojuan Wang, Wenzhuo He, Zining Wang, Jin-Xin Bei, Peng Huang, Jinyun Liu, Xiaojun Xia.
      The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.
    Keywords:  24(S),25-epoxycholesterol; CP: Cancer; CP: Immunology; antitumor immunity; reactive oxygen species; squalene epoxidase; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2024.114094
  21. J Adv Res. 2024 Apr 15. pii: S2090-1232(24)00157-7. [Epub ahead of print]
    Sweet regulation - The emerging immunoregulatory roles of hexoses.
    Junjie Xu, Yuening Zhao, Randall Tyler Mertens, Yimin Ding, Peng Xiao.
       BACKGROUND: It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells.
    AIM OF REVIEW: Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.
    Keywords:  Cancer; Hexose; Immune cell; Inflammation; Metabolism
    DOI:  https://doi.org/10.1016/j.jare.2024.04.014
  22. PLoS Pathog. 2024 Apr 15. 20(4): e1011829
    Progression of herpesvirus infection remodels mitochondrial organization and metabolism.
    Simon Leclerc, Alka Gupta, Visa Ruokolainen, Jian-Hua Chen, Kari Kunnas, Axel A Ekman, Henri Niskanen, Ilya Belevich, Helena Vihinen, Paula Turkki, Ana J Perez-Berna, Sergey Kapishnikov, Elina Mäntylä, Maria Harkiolaki, Eric Dufour, Vesa Hytönen, Eva Pereiro, Tony McEnroe, Kenneth Fahy, Minna U Kaikkonen, Eija Jokitalo, Carolyn A Larabell, Venera Weinhardt, Salla Mattola, Vesa Aho, Maija Vihinen-Ranta.
      Viruses target mitochondria to promote their replication, and infection-induced stress during the progression of infection leads to the regulation of antiviral defenses and mitochondrial metabolism which are opposed by counteracting viral factors. The precise structural and functional changes that underlie how mitochondria react to the infection remain largely unclear. Here we show extensive transcriptional remodeling of protein-encoding host genes involved in the respiratory chain, apoptosis, and structural organization of mitochondria as herpes simplex virus type 1 lytic infection proceeds from early to late stages of infection. High-resolution microscopy and interaction analyses unveiled infection-induced emergence of rough, thin, and elongated mitochondria relocalized to the perinuclear area, a significant increase in the number and clustering of endoplasmic reticulum-mitochondria contact sites, and thickening and shortening of mitochondrial cristae. Finally, metabolic analyses demonstrated that reactivation of ATP production is accompanied by increased mitochondrial Ca2+ content and proton leakage as the infection proceeds. Overall, the significant structural and functional changes in the mitochondria triggered by the viral invasion are tightly connected to the progression of the virus infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1011829
  23. Inflamm Res. 2024 Apr 15.
    Impacts of liver macrophages, gut microbiota, and bile acid metabolism on the differences in iHFC diet-induced MASH progression between TSNO and TSOD mice.
    Naoya Igarashi, Kaichi Kasai, Yuki Tada, Koudai Kani, Miyuna Kato, Shun Takano, Kana Goto, Yudai Matsuura, Mayuko Ichimura-Shimizu, Shiro Watanabe, Koichi Tsuneyama, Yukihiro Furusawa, Yoshinori Nagai.
       BACKGROUND: Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH.
    AIM: To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice.
    METHODS: We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet.
    RESULTS: TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding.
    CONCLUSIONS: The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development.
    Keywords:   Akkermansia muciniphila ; Bile acid; Fibrosis; Gut microbiota; Macrophage; Metabolic dysfunction associated steatohepatitis
    DOI:  https://doi.org/10.1007/s00011-024-01884-7
  24. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2341457
    Dietary fiber guar gum-induced shift in gut microbiota metabolism and intestinal immune activity enhances susceptibility to colonic inflammation.
    Devendra Paudel, Divek V T Nair, Sangshan Tian, Fuhua Hao, Umesh K Goand, Grace Joseph, Eleni Prodes, Zhi Chai, Chloé E M Robert, Benoit Chassaing, Andrew D Patterson, Vishal Singh.
      With an increasing interest in dietary fibers (DFs) to promote intestinal health and the growth of beneficial gut bacteria, there is a continued rise in the incorporation of refined DFs in processed foods. It is still unclear how refined fibers, such as guar gum, affect the gut microbiota activity and pathogenesis of inflammatory bowel disease (IBD). Our study elucidated the effect and underlying mechanisms of guar gum, a fermentable DF (FDF) commonly present in a wide range of processed foods, on colitis development. We report that guar gum containing diet (GuD) increased the susceptibility to colonic inflammation. Specifically, GuD-fed group exhibited severe colitis upon dextran sulfate sodium (DSS) administration, as evidenced by reduced body weight, diarrhea, rectal bleeding, and shortening of colon length compared to cellulose-fed control mice. Elevated levels of pro-inflammatory markers in both serum [serum amyloid A (SAA), lipocalin 2 (Lcn2)] and colon (Lcn2) and extensive disruption of colonic architecture further affirmed that GuD-fed group exhibited more severe colitis than control group upon DSS intervention. Amelioration of colitis in GuD-fed group pre-treated with antibiotics suggest a vital role of intestinal microbiota in GuD-mediated exacerbation of intestinal inflammation. Gut microbiota composition and metabolite analysis in fecal and cecal contents, respectively, revealed that guar gum primarily enriches Actinobacteriota, specifically Bifidobacterium. Guar gum also altered multiple genera belonging to phyla Bacteroidota and Firmicutes. Such shift in gut microbiota composition favored luminal accumulation of intermediary metabolites succinate and lactate in the GuD-fed mice. Colonic IL-18 and tight junction markers were also decreased in the GuD-fed group. Importantly, GuD-fed mice pre-treated with recombinant IL-18 displayed attenuated colitis. Collectively, unfavorable changes in gut microbiota activity leading to luminal accumulation of lactate and succinate, reduced colonic IL-18, and compromised gut barrier function following guar gum feeding contributed to increased colitis susceptibility.
    Keywords:  Added fiber; Bifidobacterium; dysbiosis; inflammatory bowel disease; interleukin-18 (IL-18); lactate; succinate
    DOI:  https://doi.org/10.1080/19490976.2024.2341457
  25. J Clin Invest. 2024 Apr 15. pii: e173934. [Epub ahead of print]134(8):
    VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis.
    Melissa M Wolf, Matthew Z Madden, Emily N Arner, Jackie E Bader, Xiang Ye, Logan Vlach, Megan L Tigue, Madelyn D Landis, Patrick B Jonker, Zaid Hatem, KayLee K Steiner, Dakim K Gaines, Bradley I Reinfeld, Emma S Hathaway, Fuxue Xin, M Noor Tantawy, Scott M Haake, Eric Jonasch, Alexander Muir, Vivian L Weiss, Kathryn E Beckermann, W Kimryn Rathmell, Jeffrey C Rathmell.
      Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl-deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl-KO tumors showed reduced activation and a lower response to anti-programmed cell death 1 (anti-PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell-specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.
    Keywords:  Cancer; Macrophages; Metabolism; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI173934
  26. Redox Biol. 2024 Mar 12. pii: S2213-2317(24)00099-5. [Epub ahead of print]72 103123
    Redox regulation of macrophages.
    Nhien Tran, Evanna L Mills.
      Redox signaling, a mode of signal transduction that involves the transfer of electrons from a nucleophilic to electrophilic molecule, has emerged as an essential regulator of inflammatory macrophages. Redox reactions are driven by reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites such as fumarate and itaconate, which can post-translationally modify specific cysteine residues in target proteins. In the past decade our understanding of how ROS, RNS, and redox-sensitive metabolites control macrophage function has expanded dramatically. In this review, we discuss the latest evidence of how ROS, RNS, and metabolites regulate macrophage function and how this is dysregulated with disease. We highlight the key tools to assess redox signaling and important questions that remain.
    DOI:  https://doi.org/10.1016/j.redox.2024.103123
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