bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023–02–05
37 papers selected by
Dylan Ryan, University of Cambridge
  1. Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation.
  2. Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.
  3. Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
  4. Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
  5. A patient-centric modeling framework captures recovery from SARS-CoV-2 infection.
  6. Metabolic regulation of NK cell function: implications for immunotherapy.
  7. Arginase 1 is a key driver of immune suppression in pancreatic cancer.
  8. Weight cycling induces innate immune memory in adipose tissue macrophages.
  9. Metabolic dialogs between B cells and the tumor microenvironment: Implications for anticancer immunity.
  10. High glucose promotes regulatory T cell differentiation.
  11. Reprogramming of glucose metabolism in virus infected cells.
  12. The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.
  13. Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating JMJD3.
  14. RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1α.
  15. Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage.
  16. Inhibition of PGK1 attenuates autoimmune myocarditis by reprogramming CD4+ T cells metabolism.
  17. Obesity and dysregulated innate immune responses: impact of micronutrient deficiencies.
  18. Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.
  19. Metabolic interaction: tumor-derived lactate inhibiting CD8+ T cell cytotoxicity in a novel route.
  20. Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program.
  21. 25-hydroxycholesterol inhibits classical swine fever virus entry into porcine alveolar macrophages by depleting plasma membrane cholesterol.
  22. Endothelial cell metabolism in sepsis.
  23. Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.
  24. TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.
  25. Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.
  26. Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.
  27. Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation.
  28. Metabolic effects of CCL5 deficiency in lean and obese mice.
  29. CD8+ T cells pass the acid test.
  30. Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.
  31. Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata.
  32. GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation.
  33. Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.
  34. Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.
  35. The role of ApoE-mediated microglial lipid metabolism in brain aging and disease.
  36. NRF2 Activation Reprogrammes Defects in Oxidative Metabolism to Restore Macrophage Function in COPD.
  37. Picornavirus infection enhances aspartate by the SLC38A8 transporter to promote viral replication.
  1. Sci Adv. 2023 Feb 03. 9(5): eade8701
    Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation.
    Mack B Reynolds, Hanna S Hong, Britton C Michmerhuizen, Anna-Lisa E Lawrence, Li Zhang, Jason S Knight, Costas A Lyssiotis, Basel H Abuaita, Mary X O'Riordan.
      Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered respiratory complex II function has been implicated in cancer, diabetes, and inflammation, but regulatory mechanisms are incompletely understood. Here, we show that macrophage inflammatory activation triggers Complex II disassembly and succinate dehydrogenase subunit B loss through sequestration and selective mitophagy. Mitochondrial fission supported lipopolysaccharide-stimulated succinate dehydrogenase subunit B degradation but not sequestration. We hypothesized that this Complex II regulatory mechanism might be coordinated by the mitochondrial phospholipid cardiolipin. Cardiolipin synthase knockdown prevented lipopolysaccharide-induced metabolic remodeling and Complex II disassembly, sequestration, and degradation. Cardiolipin-depleted macrophages were defective in lipopolysaccharide-induced pro-inflammatory cytokine production, a phenotype partially rescued by Complex II inhibition. Thus, cardiolipin acts as a critical organizer of inflammatory metabolic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.ade8701
  2. Cell Rep. 2023 Jan 31. pii: S2211-1247(23)00075-X. [Epub ahead of print]42(2): 112064
    Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst.
    Kira L Tomlinson, Sebastián A Riquelme, Swikrity Upadhyay Baskota, Marija Drikic, Ian R Monk, Timothy P Stinear, Ian A Lewis, Alice S Prince.
      Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can evade immune clearance. Here, we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects the lung from excessive inflammation but compromises bacterial clearance. S. aureus is thus able to evade the innate immune response by targeting neutrophil metabolism and inducing the production of the anti-inflammatory metabolite itaconate.
    Keywords:  CP: Immunology; CP: Microbiology; NADPH oxidase; Staphylococcus aureus; itaconate; neutrophils; oxidative burst; pathogenesis; pneumonia
    DOI:  https://doi.org/10.1016/j.celrep.2023.112064
  3. Nat Immunol. 2023 Feb 02.
    Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
    Joy Edwards-Hicks, Petya Apostolova, Joerg M Buescher, Hannes Maib, Michal A Stanczak, Mauro Corrado, Ramon I Klein Geltink, Maria Elena Maccari, Matteo Villa, Gustavo E Carrizo, David E Sanin, Francesc Baixauli, Beth Kelly, Jonathan D Curtis, Fabian Haessler, Annette Patterson, Cameron S Field, George Caputa, Ryan L Kyle, Melanie Soballa, Minsun Cha, Harry Paul, Jacob Martin, Katarzyna M Grzes, Lea Flachsmann, Michael Mitterer, Liang Zhao, Frances Winkler, David Ali Rafei-Shamsabadi, Frank Meiss, Bertram Bengsch, Robert Zeiser, Daniel J Puleston, David O'Sullivan, Edward J Pearce, Erika L Pearce.
      How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-023-01419-y
  4. Nat Metab. 2023 Jan 30.
    Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness.
    Hongcheng Cheng, Yajing Qiu, Yue Xu, Li Chen, Kaili Ma, Mengyuan Tao, Luke Frankiw, Hongli Yin, Ermei Xie, Xiaoli Pan, Jing Du, Zhe Wang, Wenjie Zhu, Lu Chen, Lianjun Zhang, Guideng Li.
      The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.
    DOI:  https://doi.org/10.1038/s42255-022-00730-6
  5. Nat Immunol. 2023 Feb;24(2): 349-358
    A patient-centric modeling framework captures recovery from SARS-CoV-2 infection.
    Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) BioResource COVID-19 Collaboration
      The biology driving individual patient responses to severe acute respiratory syndrome coronavirus 2 infection remains ill understood. Here, we developed a patient-centric framework leveraging detailed longitudinal phenotyping data and covering a year after disease onset, from 215 infected individuals with differing disease severities. Our analyses revealed distinct 'systemic recovery' profiles, with specific progression and resolution of the inflammatory, immune cell, metabolic and clinical responses. In particular, we found a strong inter-patient and intra-patient temporal covariation of innate immune cell numbers, kynurenine metabolites and lipid metabolites, which highlighted candidate immunologic and metabolic pathways influencing the restoration of homeostasis, the risk of death and that of long COVID. Based on these data, we identified a composite signature predictive of systemic recovery, using a joint model on cellular and molecular parameters measured soon after disease onset. New predictions can be generated using the online tool http://shiny.mrc-bsu.cam.ac.uk/apps/covid-19-systemic-recovery-prediction-app , designed to test our findings prospectively.
    DOI:  https://doi.org/10.1038/s41590-022-01380-2
  6. Immunometabolism (Cobham). 2023 Jan;5(1): e00020
    Metabolic regulation of NK cell function: implications for immunotherapy.
    Hyogon Sohn, Megan A Cooper.
      Natural killer (NK) cells are innate immune lymphocytes capable of rapidly responding to tumors and infection without prior sensitization. There is increasing interest and success in harnessing NK cell function for the treatment of disease, in particular cancers. NK cell activation is dependent on integration of signals through cytokine and germline-encoded activating and inhibitory receptors. The availability of metabolic fuels and pathways is required for NK effector functions including proliferation, killing, and production of interferon gamma (IFN-γ). An understanding of NK cell immunometabolism is thus essential for developing immunotherapy approaches that will allow for optimal effector functions in patients. Studies in mice and humans have demonstrated stimulation-dependent metabolic changes that are required for NK cell function. Here we review the most recent findings in NK cell immunometabolism relevant to disease models and translation to therapy of patients.
    Keywords:  NK cells; cytokines; immune memory; immunometabolism; immunotherapy; interferon-gamma; interleukin-15
    DOI:  https://doi.org/10.1097/IN9.0000000000000020
  7. Elife. 2023 Feb 02. pii: e80721. [Epub ahead of print]12
    Arginase 1 is a key driver of immune suppression in pancreatic cancer.
    Rosa Elena Menjivar, Zeribe C Nwosu, Wenting Du, Katelyn L Donahue, Hanna S Hong, Carlos Espinoza, Kristee Brown, Ashley Velez-Delgado, Wei Yan, Fatima Lima, Allison Bischoff, Padma Kadiyala, Daniel Salas-Escabillas, Howard C Crawford, Filip Bednar, Eileen Carpenter, Yaqing Zhang, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca di Magliano.
      An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by expression of the enzyme Arginase 1 (Arg1), which we demonstrated is potently expressed in pancreatic tumor associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, Arg1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting Arginine and inhibiting T cell activation.
    Keywords:  cancer biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.80721
  8. Front Immunol. 2022 ;13 984859
    Weight cycling induces innate immune memory in adipose tissue macrophages.
    Heather L Caslin, Matthew A Cottam, Jacqueline M Piñon, Likem Y Boney, Alyssa H Hasty.
       Introduction: Weight loss improves obesity-associated diabetes risk. However, most individuals regain weight, which worsens the risk of developing diabetes and cardiovascular disease. We previously reported that male mice retain obesity-associated immunological changes even after weight loss, suggesting that immune cells may remember the state of obesity. Therefore, we hypothesized that cycles of weight gain and loss, otherwise known as weight cycling, can induce innate memory in adipose macrophages.
    Methods: Bone marrow derived macrophages were primed with palmitic acid or adipose tissue conditioned media in a culture model of innate immune memory. Mice also put on low fat or high fat diets over 14-27 weeks to induce weight gain, weight loss, and weight cycling.
    Results: Priming cells with palmitic acid or adipose tissue conditioned media from obese mice increased maximal glycolysis and oxidative phosphorylation and increased LPS-induced TNFα and IL-6 production. Palmitic acid effects were dependent on TLR4 and impaired by methyltransferase inhibition and AMPK activation. While weight loss improved glucose tolerance in mice, adipose macrophages were primed for greater activation to subsequent stimulation by LPS ex vivo as measured by cytokine production. In the model of weight cycling, adipose macrophages had elevated metabolism and secreted higher levels of basal TNFα, suggesting that weight loss can also prime macrophages for heighted activation to weight regain.
    Discussion: Together, these data suggest that weight loss following obesity can prime adipose macrophages for enhanced inflammation upon weight regain. This innate immune memory response may contribute to worsened glucose tolerance following weight cycling.
    Keywords:  adipose tissue macrophages; innate immune memory; obesity; trained innate immunity; weight cycling; weight loss
    DOI:  https://doi.org/10.3389/fimmu.2022.984859
  9. Cancer Lett. 2023 Jan 29. pii: S0304-3835(23)00027-7. [Epub ahead of print]556 216076
    Metabolic dialogs between B cells and the tumor microenvironment: Implications for anticancer immunity.
    Su Jiang, Ranran Feng, Ziying Tian, Jieyu Zhou, Wenling Zhang.
      Immunometabolism, a branch of biology describing the link between immunity and metabolism, is an emerging topic in cancer immunology. It is currently well accepted that B cells and tertiary lymph structures formed by them are associated with favorable outcomes when patients undergo cancer immunotherapy. Understanding the determinants of B-cell fate and function in cancer patients is necessary for improving cancer immunotherapy. Accumulating evidence points to the tumor microenvironment being a critical metabolic hurdle to an efficient antitumor B-cell response. At the same time, several B-cell-derived metabolites have recently been reported to inhibit anticancer immunity. In this literature review, key B-cell immunometabolism studies and the metabolic life of B cells were summarized. Then, we discussed the intrinsic metabolic pathways of B cells themselves and how the tumor microenvironment and B cells in tumors metabolically influence each other. Finally, we pointed out key questions to provide some inspiration for further study of the role of B-cell immunometabolism in the antitumor immune response.
    Keywords:  Anticancer immunity; B-Cell differentiation; B-Cell-derived metabolites; Glycolysis; Immunometabolism
    DOI:  https://doi.org/10.1016/j.canlet.2023.216076
  10. PLoS One. 2023 ;18(2): e0280916
    High glucose promotes regulatory T cell differentiation.
    Elise Pitmon, Eileen Victoria Meehan, Elham Ahmadi, Adam J Adler, Kepeng Wang.
      The consumption of processed foods and sugary sodas in Western diets correlates with an increased incidence of obesity, metabolic syndromes such as type 2 diabetes, cardiovascular diseases, and autoimmune diseases including inflammatory bowel disease and rheumatoid arthritis. All these diseases have an inflammatory component, of which T lymphocytes can play a critical role in driving. Much has been learned regarding the importance of sugar, particularly glucose, in fueling effector versus regulatory T cells that can promote or dampen inflammation, respectively. In particular, glucose and its metabolic breakdown products via glycolysis are essential for effector T cell differentiation and function, while fatty acid-fueled oxidative phosphorylation supports homeostasis and function of regulatory T cells. Nevertheless, a critical knowledge gap, given the prevalence of diabetes in Western societies, is the impact of elevated glucose concentrations on the balance between effector versus regulatory T cells. To begin addressing this, we cultured naïve CD4+ T cells with different concentrations of glucose, and examined their differentiation into effector versus regulatory lineages. Surprisingly, high glucose promoted regulatory T cell differentiation and inhibited Th1 effector differentiation. This skewing towards the regulatory lineage occurred via an indirect mechanism that depends on lactate produced by activated glycolytic T cells. Addition of lactate to the T cell differentiation process promotes the differentiation of Treg cells, and activates Akt/mTOR signaling cascade. Hence, our findings suggest the existence of a novel feedback mechanism in which lactate produced by activated, differentiating T cells skews their lineage commitment towards the regulatory fate.
    DOI:  https://doi.org/10.1371/journal.pone.0280916
  11. Mol Cell Biochem. 2023 Jan 28.
    Reprogramming of glucose metabolism in virus infected cells.
    Priya Goyal, Maitreyi S Rajala.
      Viral infection is a kind of cellular stress that leads to the changes in cellular metabolism. Many metabolic pathways in a host cell such as glycolysis, amino acid and nucleotide synthesis are altered following virus infection. Both oncogenic and non-oncogenic viruses depend on host cell glycolysis for their survival and pathogenesis. Recent studies have shown that the rate of glycolysis plays an important role in oncolysis as well by oncolytic therapeutic viruses. During infection, viral proteins interact with various cellular glycolytic enzymes, and this interaction enhances the catalytic framework of the enzymes subsequently the glycolytic rate of the cell. Increased activity of glycolytic enzymes following their interaction with viral proteins is vital for replication and to counteract the inhibition of glycolysis caused by immune response. In this review, the importance of host cell glycolysis and the modulation of glycolysis by various viruses such as oncogenic, non-oncogenic and oncolytic viruses are presented.
    Keywords:  Glucose transporters; Glucose uptake; Glycolysis; Virus replication
    DOI:  https://doi.org/10.1007/s11010-023-04669-4
  12. FASEB J. 2023 Mar;37(3): e22791
    The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.
    Lin Shen, Weiyue Chen, Jiayi Ding, Gaofeng Shu, Minjiang Chen, Zhongwei Zhao, Shuiwei Xia, Jiansong Ji.
      Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.
    Keywords:  atherosclerosis; hypoxia; macrophage polarization; metabolic reprogramming
    DOI:  https://doi.org/10.1096/fj.202201486R
  13. bioRxiv. 2023 Jan 09. pii: 2023.01.09.523264. [Epub ahead of print]
    Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating JMJD3.
    Zeina Salloum, Kristin Dauner, Neha Verma, John D Zhang, Kiran Nakka, David Valdivieso-González, Víctor Almendro-Vedia, Jeffery McDonald, Alexander Sorisky, Iván López-Montero, F Jeffrey Dilworth, Xiaohui Zha.
      Cholesterol plays an important role in regulating macrophage inflammatory responses, but the mechanism is poorly understood. Here we show that reducing cholesterol in macrophages by statins upregulates JMJD3, a H3K27me3 demethylase. We provide evidence that this upregulation involves altered mitochondrial function, particularly the ATP synthase in the inner mitochondrial membrane (IMM). ATP synthase is suppressed by statin due to reduced cholesterol levels in IMM. This promotes JMJD3 expression. We also demonstrate that reducing cholesterol in macrophages alters the epigenetic configuration or epigenome. When macrophages are classically activated (M1), statin treatment suppresses the pro-inflammatory phenotype while enhancing anti-inflammatory IL-10 expression. On the other hand, when macrophages are alternatively activated (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression of these anti-inflammatory factors correlates with H3K27me3 removal by statins in resting macrophages prior to activation. Lastly, we provide evidence that JMJD3 demethylase activity is necessary for cholesterol to modulate M1 and M2 activation in macrophages. We conclude that upregulation of JMJD3 in macrophages plays a key role in the anti-inflammatory effects of statins.
    Significance Statement: In addition to lowering the plasma LDL, statins exert a well-documented anti-inflammatory effect clinically, though the mechanism is unknown. We show here that, by decreasing cellular cholesterol content, statins reduce cholesterol in the IMM to upregulates JMJD3, which is essential for anti-inflammatory functions in macrophages. This novel mechanism may potentially operate in vivo . Bone-marrow derived cells, including macrophages, are highly proliferating and require plasma LDL and cholesterol biosynthesis to provide cholesterol for new membrane production. By lowering the plasma LDL and inhibiting HMG-CoA reductase, statin therapy could generate macrophages with relatively less cholesterol in membranes, including the IMM, thereby promoting JMJD3 expression and anti-inflammatory function. This could contribute at least in part to observed anti-inflammatory effects of statins in human population.
    DOI:  https://doi.org/10.1101/2023.01.09.523264
  14. bioRxiv. 2023 Jan 07. pii: 2023.01.06.522985. [Epub ahead of print]
    RBM43 links adipose inflammation and energy expenditure through translational regulation of PGC1α.
    Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.
      Adipose thermogenesis involves specialized mitochondrial function that counteracts metabolic disease through dissipation of chemical energy as heat. However, inflammation present in obese adipose tissue can impair oxidative metabolism. Here, we show that PGC1α, a key governor of mitochondrial biogenesis and thermogenesis, is negatively regulated at the level of mRNA translation by the little-known RNA-binding protein RBM43. Rbm43 is expressed selectively in white adipose depots that have low thermogenic potential, and is induced by inflammatory cytokines. RBM43 suppresses mitochondrial and thermogenic gene expression in a PGC1α-dependent manner and its loss protects cells from cytokine-induced mitochondrial impairment. In mice, adipocyte-selective Rbm43 disruption increases PGC1α translation, resulting in mitochondrial biogenesis and adipose thermogenesis. These changes are accompanied by improvements in glucose homeostasis during diet-induced obesity that are independent of body weight. The action of RBM43 suggests a translational mechanism by which inflammatory signals associated with metabolic disease dampen mitochondrial function and thermogenesis.
    DOI:  https://doi.org/10.1101/2023.01.06.522985
  15. Front Med (Lausanne). 2022 ;9 1075465
    Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage.
    Zesen Ye, Panxia Wang, Guodong Feng, Quan Wang, Cui Liu, Jing Lu, Jianwen Chen, Peiqing Liu.
       Background: Acute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI.
    Materials and methods: The rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI.
    Results: CTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK.
    Conclusion: These findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.
    Keywords:  AMPK; Cryptotanshinone; acute lung injury; macrophage polarization; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fmed.2022.1075465
  16. Cardiovasc Res. 2023 Feb 02. pii: cvad029. [Epub ahead of print]
    Inhibition of PGK1 attenuates autoimmune myocarditis by reprogramming CD4+ T cells metabolism.
    Yang Lu, Ning Zhao, Yuwei Wu, Shuaitao Yang, Qiongfeng Wu, Qian Dong, Yimei Du.
       AIMS: CD4+ T cells are the major drivers of cardiac-specific autoimmunity in myocarditis, specifically Th1, Treg, and most significant Th17 cells. But the molecular mechanisms of their activation remain unclear. We aimed to elucidate the regulatory role of phosphoglycerate kinase 1 (PGK1) in CD4+ T cells and experimental autoimmune myocarditis (EAM).
    METHODS AND RESULTS: EAM was induced in BALB/c mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Single-cell sequencing analysis found that glycolysis and PGK1 expression were elevated in cardiac CD4+ T and Th17 cells from myocarditis mice. Mice treated with PGK1 inhibitor NG52 showed less cardiac inflammation and fibrosis and better contractile function, as well as reduced cardiac infiltrating Th17 and Th1 cells and increased proportion of Treg. NG52 suppressed CD4+ T cell activation and differentiation of mice and myocarditis patients in vitro. Mechanistically, inhibition of PGK1 suppressed glycolytic activity and decreased pyruvate dehydrogenase kinase 1 (PDHK1) phosphorylation, thereby increasing reactive oxygen species (ROS) production in mitochondria, and thus preventing Th17 cell differentiation.
    CONCLUSION: PGK1 may act as a key metabolic regulator of CD4+ T cell differentiation, and regulates Th17 cell differentiation by regulating glycolysis and the PDHK1-ROS axis. Targeting PGK1 might be a promising strategy for the treatment of myocarditis.
    TRANSLATIONAL PERSPECTIVE: Myocarditis usually causes inflammatory damage and fibrosis of the myocardium, resulting in dilated cardiomyopathy. Activated CD4+ T cells, such as Th1, Treg, especially Th17 cells, have been shown to mediate the pathogenesis of myocarditis. We found that glycolysis and PGK1 were significantly elevated in CD4+ T and Th17 cells in hearts with myocarditis. Inhibition of PGK1 leads to decreased glycolysis and increased ROS production and regulates Th17, Th1 and Treg differentiation, which may reduce inflammatory damage and delay the progression of dilated cardiomyopathy in myocarditis patients.
    DOI:  https://doi.org/10.1093/cvr/cvad029
  17. Trends Immunol. 2023 Jan 26. pii: S1471-4906(23)00003-0. [Epub ahead of print]
    Obesity and dysregulated innate immune responses: impact of micronutrient deficiencies.
    Frank Vrieling, Rinke Stienstra.
      Obesity is associated with the development of various complications, including diabetes, atherosclerosis, and an increased risk for infections, driven by dysfunctional innate immune responses. Recent insights have revealed that the availability of nutrients is a key determinant of innate immune cell function. Although the presence of obesity is associated with overnutrition of macronutrients, several micronutrient-deficiencies, including Vitamin D and zinc, are often present. Micronutrients have been attributed important immunomodulatory roles. In this review, we summarize current knowledge of the immunomodulatory effects of Vitamin D and zinc. We also suggest future lines of research to further improve our understanding of these micronutrients; this may serve as a stepping-stone to explore micronutrient supplementation to improve innate immune cell function during obesity.
    Keywords:  immunometabolism; macrophages; micronutrient deficiencies; obesity
    DOI:  https://doi.org/10.1016/j.it.2023.01.003
  18. Exp Mol Med. 2023 Feb 01.
    Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling.
    Prashanta Silwal, Young Jae Kim, Yoon Jee Lee, In Soo Kim, Sang Min Jeon, Taylor Roh, Jin Kyung Kim, Min Joung Lee, Jun Young Heo, Doo Sin Jo, Sang-Hee Lee, Dong-Hyung Cho, Jin Man Kim, Yong Tae Kwon, Eun-Kyeong Jo.
      The Arg/N-degron pathway, which is involved in the degradation of proteins bearing an N-terminal signal peptide, is connected to p62/SQSTM1-mediated autophagy. However, the impact of the molecular link between the N-degron and autophagy pathways is largely unknown in the context of systemic inflammation. Here, we show that chemical mimetics of the N-degron Nt-Arg pathway (p62 ligands) decreased mortality in sepsis and inhibited pathological inflammation by activating mitophagy and immunometabolic remodeling. The p62 ligands alleviated systemic inflammation in a mouse model of lipopolysaccharide (LPS)-induced septic shock and in the cecal ligation and puncture model of sepsis. In macrophages, the p62 ligand attenuated the production of proinflammatory cytokines and chemokines in response to various innate immune stimuli. Mechanistically, the p62 ligand augmented LPS-induced mitophagy and inhibited the production of mitochondrial reactive oxygen species in macrophages. The p62 ligand-mediated anti-inflammatory, antioxidative, and mitophagy-activating effects depended on p62. In parallel, the p62 ligand significantly downregulated the LPS-induced upregulation of aerobic glycolysis and lactate production. Together, our findings demonstrate that p62 ligands play a critical role in the regulation of inflammatory responses by orchestrating mitophagy and immunometabolic remodeling.
    DOI:  https://doi.org/10.1038/s12276-023-00929-x
  19. Signal Transduct Target Ther. 2023 Feb 03. 8(1): 52
    Metabolic interaction: tumor-derived lactate inhibiting CD8+ T cell cytotoxicity in a novel route.
    Ke Wang, Yong Zhang, Zhi-Nan Chen.
      
    DOI:  https://doi.org/10.1038/s41392-023-01320-y
  20. J Adv Res. 2023 02;pii: S2090-1232(22)00108-4. [Epub ahead of print]44 213-225
    Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program.
    Huirui Wang, Yinghui Gao, Li Wang, Yang Yu, Jiaozhen Zhang, Chunyu Liu, Yaxin Song, Haochuan Xu, Jingcheng Wang, Hongxiang Lou, Ting Dong.
       INTRODUCTION: Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-fibrotic macrophages.
    OBJECTIVES: To identify the alteration of immunometabolism in the pulmonary macrophages and investigate the feasibility of specific inhibition of M2 activation of macrophages as an effective anti-PF strategy in vivo.
    METHODS: The high-content screening system was used to select lung-specific homing compounds that can modulate macrophage polarization. Imaging mass spectrometry (IMS) conjugated with chemical proteomics approach was conducted to explore the cells and proteins targeted by diphenyleneiodonium chloride (DPI). A bleomycin-induced fibrotic mouse model was established to examine the in vivo effect of DPI.
    RESULTS: Pulmonary macrophages of PF at late stage exhibited predominantly the M2 phenotype with decreased glycolysis metabolism. DPI was demonstrated to inhibit profibrotic activation of macrophages in the preliminary screening. Notably, IMS conjugated with chemical proteomics approach revealed DPI specifically targeted pulmonary macrophages, leading to the efficient protection from bleomycin-induced pulmonary fibrosis in mice. Mechanistically, DPI upregulated glycolysis and suppressed M2 programming in fibrosis mice, thus resulting in pro-fibrotic cytokine inhibition, hydroxyproline biosynthesis, and collagen deposition, with a concomitant increase in alveolar airspaces.
    CONCLUSIONS: DPI mediated glycolysis in lung and accordingly suppressed M2 programming, resulting in improved lung fibrosis.
    Keywords:  Chemical proteomics; Diphenyleneiodonium chloride; Imaging mass spectrometry; Lung fibrosis
    DOI:  https://doi.org/10.1016/j.jare.2022.04.012
  21. Vet Microbiol. 2023 Jan 24. pii: S0378-1135(23)00020-2. [Epub ahead of print]278 109668
    25-hydroxycholesterol inhibits classical swine fever virus entry into porcine alveolar macrophages by depleting plasma membrane cholesterol.
    Liang Zhang, Yanyan Yi, Tao Wang, Mengzhao Song, Kangkang Guo, Yanming Zhang.
      Classical swine fever virus (CSFV) is an enveloped positive-sense RNA virus belonging to the Flaviviridae family. The virus utilizes cellular lipids and manipulates host lipid metabolism to ensure its replication, especially during virus invasion and replication steps. Therefore, identification of the molecular lipid metabolism pathways that are suitable targets is critical for the development of anti-CSFV therapeutics. In this study, we screened the anti-CSFV activity of 12 compounds targeting synthesis of cholesterol and fatty acids, cholesterol esters, and cholesterol transport. We found that 25-hydroxycholesterol (25HC), a regulator of cholesterol metabolism and transport, has potent anti-CSFV activity. Mechanistically, we showed that 25HC inhibited CSFV proliferation by blocking the entry of virions into porcine alveolar macrophages (3D4/21) by decreasing cholesterol abundance in the plasma membrane through activation of acyl-CoA:cholesterol acyltransferase (ACAT). Finally, we revealed that cholesterol 25-hydroxylase (CH25H), a redox enzyme that mediates 25HC production, also restricted CSFV infection via both enzyme activity-dependent and -independent mechanisms. Collectively, our results shed light on the mechanisms by which 25HC inhibits CSFV entry into cells and suggests a potential new therapeutic method against CSFV infection.
    Keywords:  25-hydroxycholesterol; Cholesterol 25-hydroxylase; Classical swine fever virus; Plasma membrane cholesterol
    DOI:  https://doi.org/10.1016/j.vetmic.2023.109668
  22. World J Emerg Med. 2023 ;14(1): 10-16
    Endothelial cell metabolism in sepsis.
    Jue-Xian Wei, Hui-Lin Jiang, Xiao-Hui Chen.
       BACKGROUND: Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure. Endothelial cells (ECs) exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.
    METHODS: Web of Science and PubMed were searched from inception to October 1, 2022. The search was limited to the English language only. Two reviewers independently identified studies related to EC metabolism in sepsis. The exclusion criteria were duplicate articles according to multiple search criteria.
    RESULTS: Sixty articles were included, and most of them were cell and animal studies. These studies reported the role of glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism in EC homeostasis. including glycolysis, oxidative phosphorylation, fatty acid metabolism and amino acid metabolism. However, dysregulation of EC metabolism can contribute to sepsis progression.
    CONCLUSION: There are few clinical studies on EC metabolism in sepsis. Related research mainly focuses on basic research, but some scientific problems have also been clarified. Therefore, this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.
    Keywords:  Amino acid metabolism; Endothelium; Fatty acid metabolism; Glycolysis; Metabolism; Oxidative phosphorylation; Sepsis
    DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2023.019
  23. Sci Rep. 2023 Jan 30. 13(1): 1653
    Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.
    Tadamichi Kasuya, Shigeru Tanaka, Jun Tamura, Keishi Etori, Jumpei Shoda, Koto Hattori, Yusuke Endo, Masayuki Kitajima, Takahiro Kageyama, Taro Iwamoto, Masaya Yokota, Arifumi Iwata, Akira Suto, Kotaro Suzuki, Harumi Suzuki, Steven F Ziegler, Hiroshi Nakajima.
      Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although TSLP does not affect thymic Treg differentiation, TSLP receptor-deficient induced Treg cells derived from naïve CD4+ T cells are less activated in an adoptive transfer model of colitis. Mechanistically, TSLP activates induced Treg cells partially through mTORC1 activation and fatty acid uptake. Thus, TSLP modulates the activation status of induced Treg through the enhanced uptake of fatty acids to maintain homeostasis in the large intestine.
    DOI:  https://doi.org/10.1038/s41598-023-28987-1
  24. Exp Mol Med. 2023 Feb 01.
    TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.
    Chenfei Wang, Jia Lu, Xudong Sha, Yu Qiu, Hongzhuan Chen, Zhihua Yu.
      Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer's disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1flox/flox; Cx3cr1cre-ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele.
    DOI:  https://doi.org/10.1038/s12276-023-00935-z
  25. Cancer Immunol Immunother. 2023 Feb 02.
    Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.
    Chao Wang, Linxuan Xue, Wenqiang Zhu, Lina Liu, Shuhua Zhang, Daya Luo.
      Globally, breast cancer is one of the leading causes of cancer death in women. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. Lactate in tumors mainly comes from glycolysis and glutaminolysis. Using multiomics data analysis, we found that lactate is mainly derived from glycolysis in breast cancer. Single-cell transcriptome analysis found that breast cancer cells with higher malignancy, especially those in the cell cycle, have higher expression levels of glycolytic metabolic enzymes. Combined with clinical data analysis, it was found that the expression of the lactate transporter SLC16A3 is correlated with breast cancer molecular subtypes and immune infiltration. Among 22 immune cells, macrophages are the most abundant immune cells in breast cancer tissues, and the proportion of M1 macrophages is lower in the high SLC16A3 expression group. Finally, in vitro experiments confirmed that lactate could inhibit the expression of M1 macrophage markers at both RNA and protein levels. In conclusion, we found that lactate produced by glycolysis regulates the polarization of inflammatory macrophages in breast cancer.
    Keywords:  Breast cancer; Lactate; Macrophage polarization; Metabolic reprogramming; Multiomics
    DOI:  https://doi.org/10.1007/s00262-023-03382-x
  26. Blood. 2023 Feb 03. pii: blood.2022017584. [Epub ahead of print]
    Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.
    Pedro Gonzalez-Menendez, Ira Phadke, Meagan E Olive, Axel Joly, Julien Papoin, Hongxia Yan, Jérémy Galtier, Jessica Platon, Sun Woo Sophie Kang, Kathy L McGraw, Marie Daumur, Marie Pouzolles, Taisuke Kondo, Stéphanie Boireau, Franciane Paul, David J Young, Sylvain Lamure, Raghavendra G Mirmira, Anu Narla, Guillaume Cartron, Cynthia E Dunbar, Myriam Boyer-Clavel, Natalie Porat-Shliom, Valerie Dardalhon, Valerie S Zimmermann, Marc Sitbon, Thomas Dever, Narla Mohandas, Lydie M Da Costa, Namrata D Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor.
      Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors--by inhibition of deoxyhypusine synthase--abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.
    DOI:  https://doi.org/10.1182/blood.2022017584
  27. Immunity. 2023 Feb 01. pii: S1074-7613(23)00017-1. [Epub ahead of print]
    Ambient oxygen levels regulate intestinal dysbiosis and GVHD severity after allogeneic stem cell transplantation.
    Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos da Silva, Marcel R M van den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M Schmidt, Yatrik M Shah, Robert R Jenq, Gregory Dick, Pavan Reddy.
      The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in a host intestinal HIF-1α- and a microbiome-dependent manner. Regulation of intestinal ambient oxygen levels with oral iron chelation mitigated dysbiosis and reduced the severity of the GI GVHD. Thus, targeting ambient intestinal oxygen levels may represent a novel, non-immunosuppressive strategy to mitigate T cell-driven intestinal diseases.
    Keywords:  T cell-mediated gastrointestinal (GI) diseases; allogeneic; germ-free; graft-versus-host host disease; hypoxia; iron chelation; microbiome; oxygen; tissue tolerance; transplantation
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.007
  28. Front Immunol. 2022 ;13 1059687
    Metabolic effects of CCL5 deficiency in lean and obese mice.
    Hui Zhou, Xiyan Liao, Qin Zeng, Haowei Zhang, Jianfeng Song, Wanyu Hu, Xiaoxiao Sun, Yujin Ding, Dandan Wang, Yalun Xiao, Tuo Deng.
      Accumulation and activation of immunocytes in adipose tissues are essential to obesity-induced inflammation and insulin resistance. Chemokines are pivotal for the recruitment of immunocytes in adipose tissue during obesity. Chemokine (C-C motif) ligand 5 (CCL5) plays a vital role in the recruitment of immunocytes to sites of inflammation. CCL5 expression level is increased in obese adipose tissue from humans and mice. However, the role of CCL5 in obesity-induced adipose inflammation remains unclear. Our study found that the CCL5 expression level was increased in the epididymal white adipose tissue (eWAT) of obese mice, particularly in CD8+ T cells. CCL5 knockout (KO) mice exhibited better glucose tolerance than wild-type (WT) mice under lean conditions. In contrast, CCL5 KO mice were more insulin resistant and had severe hepatic steatosis than WT mice under obese conditions. Increased T cells in adipose tissue heaven adipose inflammation in obese CCL5 KO mice. The compensatory increased T cell-associated chemokines may account for increased T cell content in the eWAT of obese CCL5 KO mice. These findings imply that CCL5 deficiency exacerbates adipose inflammation and impairs insulin sensitivity in the metabolic tissues of obese mice.
    Keywords:  CCL5; adipose inflammation; chemokine; insulin resistance; obesity
    DOI:  https://doi.org/10.3389/fimmu.2022.1059687
  29. Nat Metab. 2023 Jan 30.
    CD8+ T cells pass the acid test.
    Ju Hee Oh, Anne-Sophie Archambault, Ramon I Klein Geltink.
      
    DOI:  https://doi.org/10.1038/s42255-023-00738-6
  30. Nat Commun. 2023 Feb 01. 14(1): 544
    Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.
    BIOS consortium
      Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease.
    DOI:  https://doi.org/10.1038/s41467-022-35663-x
  31. PNAS Nexus. 2023 Jan;2(1): pgac297
    Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata.
    Jerry Tsai, Sadakatali Gori, Jesse Alt, Sandhya Tiwari, Jitesh Iyer, Rashmi Talwar, Denish Hinsu, Kailash Ahirwar, Swayam Mohanty, Chintan Khunt, Brijesh Sutariya, Kaushal Jani, Venkatesha Venkatasubbaiah, Ashok Patel, Jasmin Meghapara, Kaushal Joshi, Rajanikanta Sahu, Vijay Rana, Prashant Nigade, Ravi S Talluri, Kadiyala V S N Murty, Kiritkumar Joshi, Vikram Ramanathan, Ang Li, Nasif Islam, Ivan Snajdr, Pavel Majer, Rana Rais, Barbara S Slusher, Luis A Garza.
      Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+  T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
    Keywords:  alopecia areata; anagen; cytokine; cytotoxicity; double-stranded RNA; hair cycle; hair growth; immunosuppression; inflammation; interferon; interleukin; itaconate; keratinocyte; pharmacokinetics; polyinosinic–polycytidylic acid; prodrug; stability; telogen; topical
    DOI:  https://doi.org/10.1093/pnasnexus/pgac297
  32. Nature. 2023 Feb;614(7946): E1-E11
    GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation.
    Wei Xu, Chirag H Patel, Jesse Alt, Liang Zhao, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Jiayu Wen, Richard L Blosser, Ada J Tam, Jonathan D Powell.
      
    DOI:  https://doi.org/10.1038/s41586-022-05602-3
  33. Cell Rep. 2023 Feb 02. pii: S2211-1247(23)00089-X. [Epub ahead of print]42(2): 112078
    Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway.
    Ling-Ran Kong, Xiao-Hui Chen, Qing Sun, Kai-Yuan Zhang, Lian Xu, Liliqiang Ding, Yan-Ping Zhou, Ze-Bei Zhang, Jing-Rong Lin, Ping-Jin Gao.
      Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.
    Keywords:  C3aR; C5aR; CP: Metabolism; Tregs; adipocyte browning; inosine/A2aR pathway
    DOI:  https://doi.org/10.1016/j.celrep.2023.112078
  34. medRxiv. 2023 Jan 09. pii: 2023.01.08.23284316. [Epub ahead of print]
    Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.
    Edwin Ardiansyah, Julian Avila Pacheco, Le Thanh Hoang Nhat, Sofiati Dian, Dao Nguyen Vinh, Hoang Thanh Hai, Kevin Bullock, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Tran Thi Hong Chau, Nguyen Duc Bang, Ahmad Rizal Ganiem, Rovina Ruslami, Valerie Acm Koeken, Raph L Hamers, Darma Imran, Kartika Maharani, Vinod Kumar, Clary B Clish, Reinout van Crevel, Guy Thwaites, Arjan van Laarhoven, Nguyen Thuy Thuong Thuong.
       Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.
    Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.
    Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.
    Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy.
    Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).
    DOI:  https://doi.org/10.1101/2023.01.08.23284316
  35. Immunometabolism (Cobham). 2023 Jan;5(1): e00018
    The role of ApoE-mediated microglial lipid metabolism in brain aging and disease.
    Jui-Hung Jimmy Yen, I-Chen Ivorine Yu.
      Microglia are a unique population of immune cells resident in the brain that integrate complex signals and dynamically change phenotypes in response to the brain microenvironment. In recent years, single-cell sequencing analyses have revealed profound cellular heterogeneity and context-specific transcriptional plasticity of microglia during brain development, aging, and disease. Emerging evidence suggests that microglia adapt phenotypic plasticity by flexibly reprogramming cellular metabolism to fulfill distinct immune functions. The control of lipid metabolism is central to the appropriate function and homeostasis of the brain. Microglial lipid metabolism regulated by apolipoprotein E (ApoE), a crucial lipid transporter in the brain, has emerged as a critical player in regulating neuroinflammation. The ApoE gene allelic variant, ε4, is associated with a greater risk for neurodegenerative diseases. In this review, we explore novel discoveries in microglial lipid metabolism mediated by ApoE. We elaborate on the functional impact of perturbed microglial lipid metabolism on the underlying pathogenesis of brain aging and disease.
    Keywords:  apolipoprotein E; lipid metabolism; microglia
    DOI:  https://doi.org/10.1097/IN9.0000000000000018
  36. Am J Respir Crit Care Med. 2023 Feb 01.
    NRF2 Activation Reprogrammes Defects in Oxidative Metabolism to Restore Macrophage Function in COPD.
    Eilise M Ryan, Pranvera Sadiku, Patricia Coelho, Emily R Watts, Ailiang Zhang, Andrew J M Howden, Manuel A Sanchez-Garcia, Martin Bewley, Joby Cole, Brian J McHugh, Wesley Vermaelen, Bart Ghesquiere, Peter Carmeliet, Giovanny Rodriguez Blanco, Alex Von Kriegsheim, Yolanda Sanchez, William Rumsey, James F Callahan, George Cooper, Nicholas Parkinson, Kenneth Baillie, Doreen A Cantrell, John McCafferty, Gourab Choudhury, Dave Singh, David H Dockrell, Moira K B Whyte, Sarah R Walmsley.
       RATIONALE: COPD (Chronic Obstructive Pulmonary Disease) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated.
    OBJECTIVES: Through the study of COPD alveolar (AM) and peripheral monocyte-derived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance.
    METHODS: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling.
    RESULTS: We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH generating enzyme, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function.
    CONCLUSION: In COPD an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.
    Keywords:  COPD; Macrophage; Malic Enzyme 1; Metabolism; nuclear factor erythroid 2–related factor 2 (Nrf2)
    DOI:  https://doi.org/10.1164/rccm.202203-0482OC
  37. PLoS Pathog. 2023 Feb 03. 19(2): e1011126
    Picornavirus infection enhances aspartate by the SLC38A8 transporter to promote viral replication.
    Huisheng Liu, Zixiang Zhu, Qiao Xue, Fan Yang, Weijun Cao, Zhaoning Xue, Xiangtao Liu, Haixue Zheng.
      Foot-and-mouth disease, a class of animal diseases, is caused by foot-and-mouth disease virus (FMDV). The metabolic changes during FMDV infection remain unclear. Here, PK-15 cells, serum, and tonsils infected with FMDV were analyzed by metabolomics. A total of 284 metabolites in cells were significantly changed after FMDV infection, and most of them belong to amino acids and nucleotides. Further studies showed that FMDV infection significantly enhanced aspartate in vitro and in vivo. The amino acid transporter solute carrier family 38 member 8 (SLC38A8) was responsible for FMDV-upregulated aspartate. Enterovirus 71 (EV71) and Seneca Valley virus (SVV) infection also enhanced aspartate by SLC38A8. Aspartate aminotransferase activity was also elevated in FMDV-, EV71-, and SVV-infected cells, which may lead to reversible transition between the TCA cycle and amino acids synthesis. Aspartate and SLC38A8 were essential for FMDV, EV71, and SVV replication in cells. In addition, aspartate and SLC38A8 also promoted FMDV and EV71 replication in mice. Detailed analysis indicated that FMDV infection promoted the transfer of mTOR to lysosome to enhance interaction between mTOR and Rheb, and activated PI3K/AKT/TSC2/Rheb/mTOR/p70S6K1 pathway to promote viral replication. The mTORC1 signaling pathway was responsible for FMDV-induced SLC38A8 protein expression. For the first time, our data identified metabolic changes during FMDV infection. These data identified a novel mechanism used by FMDV to upregulate aspartate to promote viral replication and will provide new perspectives for developing new preventive strategies.
    DOI:  https://doi.org/10.1371/journal.ppat.1011126
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