bims-imicid 2024-06-30 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–06–30
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.
Immunometabolism in atherosclerosis: a new understanding of an old disease.
Itaconate and dimethyl itaconate upregulate IL-6 production in the LPS-induced inflammation in mice.
Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation.
Linoleic acid-derived diol 12,13-DiHOME enhances NLRP3 inflammasome activation in macrophages.
Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.
Respiratory Virus-Induced PARP1 Alters DC Metabolism and Antiviral Immunity Inducing Pulmonary Immunopathology.
Promising roles of combined therapy based on immune response and iron metabolism in systemic lupus erythematosus.
Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis.
Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.
Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.
Dengue Virus Dependence on Glucokinase Activity and Glycolysis Confers Sensitivity to NAD(H) Biosynthesis Inhibitors.
A commensal-derived sugar protects against metabolic disease.
Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation.
Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.
Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia.
IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.
Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.
Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.
Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.
Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma.

Nature. 2024 Jun 26.

Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair.

Parul Mehrotra, Sophia Maschalidi, Laura Boeckaerts, Christian Maueröder, Rochelle Tixeira, Jonathan Pinney, Javier Burgoa Cardás, Vladimir Sukhov, Yunus Incik, Christopher J Anderson, Bing Hu, Burcu N Keçeli, Amanda Goncalves, Lieselotte Vande Walle, Nina Van Opdenbosch, Alexey Sergushichev, Esther Hoste, Umang Jain, Mohamed Lamkanfi, Kodi S Ravichandran.

Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases1-4. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro-1), we identify unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.

DOI: https://doi.org/10.1038/s41586-024-07585-9
Trends Biochem Sci. 2024 Jun 26. pii: S0968-0004(24)00146-4. [Epub ahead of print]

Immunometabolism in atherosclerosis: a new understanding of an old disease.

Michelangelo Certo, Mahsa Rahimzadeh, Claudio Mauro.

  Atherosclerosis, a chronic inflammatory condition, remains a leading cause of death globally, necessitating innovative approaches to target pro-atherogenic pathways. Recent advancements in the field of immunometabolism have highlighted the crucial interplay between metabolic pathways and immune cell function in atherogenic milieus. Macrophages and T cells undergo dynamic metabolic reprogramming to meet the demands of activation and differentiation, influencing plaque progression. Furthermore, metabolic intermediates intricately regulate immune cell responses and atherosclerosis development. Understanding the metabolic control of immune responses in atherosclerosis, known as athero-immunometabolism, offers new avenues for preventive and therapeutic interventions. This review elucidates the emerging intricate interplay between metabolism and immunity in atherosclerosis, underscoring the significance of metabolic enzymes and metabolites as key regulators of disease pathogenesis and therapeutic targets.

Keywords:  chronic inflammatory disease; immune response; metabolic pathways; metabolic reprogramming; metabolites; therapeutic targets

DOI:  https://doi.org/10.1016/j.tibs.2024.06.003
J Leukoc Biol. 2024 Jun 28. pii: qiae149. [Epub ahead of print]

Itaconate and dimethyl itaconate upregulate IL-6 production in the LPS-induced inflammation in mice.

Maxim Nosenko, Denis Anisov, Ekaterina Gubernatorova, Ekaterina Gorshkova, Yi-Rong Zeng, Dan Ye, Pu Wang, David Finlay, Marina Drutskaya, Sergei Nedospasov.

  Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered as potential therapeutic agents for treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knock-out mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate (ITA) and its derivative dimethyl itaconate (DI) in a mouse model of LPS-induced inflammation. The data show that administration of ITA or DI controls systemic production of multiple cytokines, including increased IL-10 production. However, only DI was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of ITA or DI in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to ITA or DI was not responsible for IL-6 upregulation. However, inhibition of SDH with dimethyl malonate (DM) also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative DI on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies.

Keywords:  SDH; cytokines; immunometabolism

DOI:  https://doi.org/10.1093/jleuko/qiae149
Sci Rep. 2024 06 22. 14(1): 14405

Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation.

Bruno Chausse, Nikolai Malorny, Andrea Lewen, Gernot Poschet, Nikolaus Berndt, Oliver Kann.

  Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30-70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.

Keywords:  Glycolysis; Immunometabolism; Lactate oxidation; Microglia; Neuronal oscillations

DOI:  https://doi.org/10.1038/s41598-024-64872-1
FASEB J. 2024 Jul 15. 38(13): e23748

Linoleic acid-derived diol 12,13-DiHOME enhances NLRP3 inflammasome activation in macrophages.

Robert Valencia, Joshua W Kranrod, Liye Fang, Amro M Soliman, Brandon Azer, Xavier Clemente-Casares, John M Seubert.

  12,13-dihydroxy-9z-octadecenoic acid (12,13-DiHOME) is a linoleic acid diol derived from cytochrome P-450 (CYP) epoxygenase and epoxide hydrolase (EH) metabolism. 12,13-DiHOME is associated with inflammation and mitochondrial damage in the innate immune response, but how 12,13-DiHOME contributes to these effects is unclear. We hypothesized that 12,13-DiHOME enhances macrophage inflammation through effects on NOD-like receptor protein 3 (NLRP3) inflammasome activation. To test this hypothesis, we utilized human monocytic THP1 cells differentiated into macrophage-like cells with phorbol myristate acetate (PMA). 12,13-DiHOME present during lipopolysaccharide (LPS)-priming of THP1 macrophages exacerbated nigericin-induced NLRP3 inflammasome activation. Using high-resolution respirometry, we observed that priming with LPS+12,13-DiHOME altered mitochondrial respiratory function. Mitophagy, measured using mito-Keima, was also modulated by 12,13-DiHOME present during priming. These mitochondrial effects were associated with increased sensitivity to nigericin-induced mitochondrial depolarization and reactive oxygen species production in LPS+12,13-DiHOME-primed macrophages. Nigericin-induced mitochondrial damage and NLRP3 inflammasome activation in LPS+12,13-DiHOME-primed macrophages were ablated by the mitochondrial calcium uniporter (MCU) inhibitor, Ru265. 12,13-DiHOME present during LPS-priming also enhanced nigericin-induced NLRP3 inflammasome activation in primary murine bone marrow-derived macrophages. In summary, these data demonstrate a pro-inflammatory role for 12,13-DiHOME by enhancing NLRP3 inflammasome activation in macrophages.

Keywords:  cytochrome P‐450 CYP2J2; epoxide hydrolases; inflammasomes; inflammation; linoleic acid; macrophages; mitochondria; oxylipins

DOI:  https://doi.org/10.1096/fj.202301640RR
Biochem Biophys Res Commun. 2024 Jun 14. pii: S0006-291X(24)00804-0. [Epub ahead of print]726 150268

Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.

Sayak Ghosh, Rittick Dutta, Debapriya Ghatak, Devyani Goswami, Rudranil De.

  Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial association, in Tumor Microenvironment (TME) that regulate cancer progression. Conventional DC subtypes cross-present tumor-associated antigens to activate lymphocytes. However, plasmacytoid DCs participate in both pro- and anti-tumor signaling where mitochondrial reactive oxygen species (mtROS) play crucial role. CTLA-4, CD-47 and other surface-receptors of DC negatively regulates T-cell. Increased glycolysis-mediated mitochondrial citrate buildup and translocation to cytosol with augmented NADPH, enhances mitochondrial fatty acid synthesis fueling DCs. Different DC subtypes and stages, exhibit variable mitochondrial content, membrane potential, structural dynamics and bioenergetic metabolism regulated by various cytokine stimulation, e.g., GM-CSF, IL-4, etc. CD8α+ cDC1s augmented oxidative phosphorylation (OXPHOS) which diminishes at advance effector stages. Glutaminolysis in mitochondria supplement energy in DCs but production of kynurenine and other oncometabolites leads to immunosuppression. Mitochondria-associated DAMPs cause activation of cGAS-STING pathway and inflammasome oligomerization stimulating DC and T cells. In this study, through a comprehensive survey and critical analysis of the latest literature, the potential of DC metabolism for more effective tumor therapy is highlighted. This underscores the need for future research to explore specific therapeutic targets and potential drug candidates.

Keywords:  Cancer; Dendritic cells; Immunometabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1016/j.bbrc.2024.150268
Viruses. 2024 Jun 04. pii: 910. [Epub ahead of print]16(6):

Respiratory Virus-Induced PARP1 Alters DC Metabolism and Antiviral Immunity Inducing Pulmonary Immunopathology.

Mohamed M Mire, Srikanth Elesela, Susan Morris, Gabriel Corfas, Andrew Rasky, Nicholas W Lukacs.

  Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive of altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation in RSV-infected DC. Real-time cell metabolic analysis demonstrated increased glycolysis in PARP1-/- DC after RSV infection, confirming a role for PARP1 in regulating DC metabolism. Our data show that enzymatic inhibition or genomic ablation of PARP1 resulted in increased ifnb1, il12, and il27 in RSV-infected DC which, together, promote a more appropriate anti-viral environment. PARP1-/- mice and PARP1-inhibitor-treated mice were protected against RSV-induced immunopathology including airway inflammation, Th2 cytokine production, and mucus hypersecretion. However, delayed treatment with PARP1 inhibitor in RSV-infected mice provided only partial protection, suggesting that PARP1 is most important during the earlier innate immune stage of RSV infection.

Keywords:  cell metabolism; dendritic cell; innate immunity; virus infection

DOI:  https://doi.org/10.3390/v16060910
Int Immunopharmacol. 2024 Jun 24. pii: S1567-5769(24)01002-6. [Epub ahead of print]138 112481

Promising roles of combined therapy based on immune response and iron metabolism in systemic lupus erythematosus.

Zhouhang Xing, Sheng Gao, Anzhe Zheng, Chuyan Tong, Yuan Fang, Zheng Xiang, Siyan Chen, Wenqian Wang, Chunyan Hua.

  Systemic lupus erythematosus (SLE) is an intricate autoimmune disease with diverse manifestations. Immunometabolism reprogramming contributes to the progression of SLE by regulating the phenotype and function of immune cells. Dysregulated iron metabolism is implicated in SLE pathogenesis, affecting both systemic and immune cell-specific iron homeostasis. This review explores the systemic and cellular iron handling and regulation. Additionally, the advancements regarding iron metabolism in SLE with a focus on the distinct subsets of immune cells are highlighted. By gaining insight into the interplay between iron dysregulation and immune dysfunction, the potential therapeutic avenues may be unveiled. However, challenges remain in elucidating cell-specific iron metabolic reprogramming and its contribution to SLE pathogenesis needs further research for personalized therapeutic interventions and biomarker discovery. This review provides an in-depth understanding of immune cell-specific regulatory mechanisms of iron metabolism and new insights in current challenges as well as possible clinical applications.

Keywords:  Drug; Immune cell; Immunomodulation; Iron metabolism; Systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.intimp.2024.112481
Elife. 2024 Jun 26. pii: RP89319. [Epub ahead of print]12

Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis.

Mariano Maio, Joaquina Barros, Marine Joly, Zoi Vahlas, José Luis Marín Franco, Melanie Genoula, Sarah C Monard, María Belén Vecchione, Federico Fuentes, Virginia Gonzalez Polo, María Florencia Quiroga, Mónica Vermeulen, Thien-Phong Vu Manh, Rafael J Argüello, Sandra Inwentarz, Rosa Musella, Lorena Ciallella, Pablo González Montaner, Domingo Palmero, Geanncarlo Lugo Villarino, María Del Carmen Sasiain, Olivier Neyrolles, Christel Vérollet, Luciana Balboa.

  During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with Mycobacterium tuberculosis (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.

Keywords:  cell migration; dendritic cells; glycolysis; human; immunology; immunometabolism; inflammation; monocytes; mouse; tuberculosis

DOI:  https://doi.org/10.7554/eLife.89319
Cell Host Microbe. 2024 Jun 18. pii: S1931-3128(24)00197-5. [Epub ahead of print]

Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.

Selene Meza-Perez, Mingyong Liu, Aaron Silva-Sanchez, Casey D Morrow, Peter G Eipers, Elliot J Lefkowitz, Travis Ptacek, Christopher D Scharer, Alexander F Rosenberg, Dave D Hill, Rebecca C Arend, Michael J Gray, Troy D Randall.

  Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.

Keywords:  Treg activation; anti-tumor responses; arginine metabolism; gut Proteobacteria; mTOR pathway; omentum

DOI:  https://doi.org/10.1016/j.chom.2024.06.003
bioRxiv. 2024 Jun 12. pii: 2024.06.10.598377. [Epub ahead of print]

Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.

Nicholas J Maurice, Jami R Erickson, Caitlin S DeJong, Florian Mair, Alexis K Taber, Marie Frutoso, Laura V Islas, Anna-Lena Bg Vigil, Richard L Lawler, M Juliana McElrath, Evan W Newell, Lucas B Sullivan, Raj Shree, Stephen A McCartney.

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.

DOI: https://doi.org/10.1101/2024.06.10.598377
Antiviral Res. 2024 Jun 21. pii: S0166-3542(24)00148-7. [Epub ahead of print] 105939

Dengue Virus Dependence on Glucokinase Activity and Glycolysis Confers Sensitivity to NAD(H) Biosynthesis Inhibitors.

Eva Ogire, Laure Perrin-Cocon, Marianne Figl, Cindy Kundlacz, Clémence Jacquemin, Sophie Hubert, Anne Aublin-Gex, Johan Toesca, Christophe Ramière, Pierre-Olivier Vidalain, Cyrille Mathieu, Vincent Lotteau, Olivier Diaz.

  Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites. Dengue virus (DENV), a mosquito-borne flavivirus responsible for dengue fever, is no exception. Previous reports have documented DENV interactions with metabolic pathways and shown in particular that glycolysis is increased in DENV-infected cells. However, underlying molecular mechanisms are still poorly characterized and dependence of DENV on this pathway has not been investigated in details yet. Here, we identified an interaction between the non-structural protein 3 (NS3) of DENV and glucokinase regulator protein (GCKR), a host protein that inhibits the liver-specific hexokinase GCK. NS3 expression was found to increase glucose consumption and lactate secretion in hepatic cell line expressing GCK. Interestingly, we observed that GCKR interaction with GCK decreases DENV replication, indicating the dependence of DENV to GCK activity and supporting the role of NS3 as an inhibitor of GCKR function. Accordingly, in the same cells, DENV replication both induces and depends on glycolysis. By targeting NAD(H) biosynthesis with the antimetabolite 6-Amino-Nicotinamide (6-AN), we decreased cellular glycolytic activity and inhibited DENV replication in hepatic cells. Infection of primary organotypic liver cultures (OLiC) from hamsters was also inhibited by 6-AN. Altogether, our results show that DENV has evolved strategies to control glycolysis in the liver, which could account for hepatic dysfunctions associated to infection. Besides, our findings suggest that lowering intracellular availability of NAD(H) could be a valuable therapeutic strategy to control glycolysis and inhibit DENV replication in the liver.

Keywords:  Dengue Virus NS3; NAD(H) metabolism; glucokinase regulator protein; glycolysis; hepatocyte; primary organotypic liver cultures

DOI:  https://doi.org/10.1016/j.antiviral.2024.105939
bioRxiv. 2024 Jun 12. pii: 2024.06.12.598703. [Epub ahead of print]

A commensal-derived sugar protects against metabolic disease.

Chin Yee Tan, Danting Jiang, Barbara S Theriot, Meghana V Rao, Neeraj K Surana.

Obesity is a worsening global epidemic that is regulated by the microbiota through unknown bacterial factors. We discovered a human-derived commensal bacterium, Clostridium immunis , that protects against metabolic disease by secreting a phosphocholine-modified exopolysaccharide. Genetic interruption of the phosphocholine biosynthesis locus ( licABC ) results in a functionally inactive exopolysaccharide, which demonstrates the critical requirement for this phosphocholine moiety. This C. immunis exopolysaccharide acts via group 3 innate lymphoid cells and modulating IL-22 levels, which results in a reduction in serum triglycerides, body weight, and visceral adiposity. Importantly, phosphocholine biosynthesis genes are less abundant in humans with obesity or hypertriglyceridemia, findings that suggest the role of bacterial phosphocholine is conserved across mice and humans. These results define a bacterial molecule-and its key structural motif-that regulates host metabolism. More broadly, they highlight how small molecules, such as phosphocholine, may help fine-tune microbiome- immune-metabolism interactions.

DOI: https://doi.org/10.1101/2024.06.12.598703
Nat Commun. 2024 Jun 25. 15(1): 5394

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.

Bam D Paneru, Julia Chini, Sam J McCright, Nicole DeMarco, Jessica Miller, Leonel D Joannas, Jorge Henao-Mejia, Paul M Titchenell, David M Merrick, Hee-Woong Lim, Mitchell A Lazar, David A Hill.

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.

DOI: https://doi.org/10.1038/s41467-024-49632-z
Int J Mol Sci. 2024 Jun 20. pii: 6808. [Epub ahead of print]25(12):

Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation.

Jaemi Kim, Ji-Yun Kim, Hye-Eun Byeon, Ji-Won Kim, Hyoun-Ah Kim, Chang-Hee Suh, Sangdun Choi, MacRae F Linton, Ju-Yang Jung.

  Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

Keywords:  atherosclerosis; cholesterol efflux; foam cells; toll-like receptor

DOI:  https://doi.org/10.3390/ijms25126808
BMB Rep. 2024 Jun 26. pii: 6203. [Epub ahead of print]

Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy.

Seon Ah Lim.

Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment (TME). In the TME, numerous distinct factors actively induce immunosuppression, restricting the efficacy of anticancer immune reactions. Recently, metabolic reprogramming of tumors has been recognized for its role in modulating the tumor microenvironment to enhance immune cell responses in the TME. Furthermore, recent elucidations underscore the critical role of metabolic limitations imposed by the tumor microenvironment on the effectiveness of antitumor immune cells, guiding the development of novel immunotherapeutic approaches. Hence, achieving a comprehensive understanding of the metabolic requirements of both cancer and immune cells within the TME is pivotal. This insight not only aids in acknowledging the current limitations of clinical practices but also significantly shapes the trajectory of future research endeavors in the domain of cancer immunotherapy. In addition, therapeutic interventions targeting metabolic limitations have exhibited promising potential as combinatory treatments across diverse cancer types. In this review, we first discuss the metabolic barriers in the TME. Second, we explore how the immune response is regulated by metabolites. Finally, we will review the current strategy for targeting metabolism to not simply inhibit tumor growth but also enhance antitumor immune responses. Thus, we could suggest potent combination therapy for improving immunotherapy with metabolic inhibitors.
bioRxiv. 2024 Jun 10. pii: 2024.06.07.597992. [Epub ahead of print]

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia.

Nadia A Lanman, Era Meco, Philip Fitchev, Andree K Kolliegbo, Meaghan M Broman, Yana Filipovich, Harish Kothandaraman, Gregory M Cresswell, Pooja Talaty, Malgorzata Antoniak, Svetlana Brumer, Alexander P Glaser, Andrew M Higgins, Brian T Helfand, Omar E Franco, Susan E Crawford, Timothy L Ratliff, Simon W Hayward, Renee E Vickman.

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45 + transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2 + and MARCO + macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2 + macrophages have significantly higher neutral lipid than TREM2 - macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2 + and MARCO + macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

DOI: https://doi.org/10.1101/2024.06.07.597992
Nat Commun. 2024 Jun 26. 15(1): 5403

IFNγ causes mitochondrial dysfunction and oxidative stress in myositis.

Catalina Abad, Iago Pinal-Fernandez, Clement Guillou, Gwladys Bourdenet, Laurent Drouot, Pascal Cosette, Margherita Giannini, Lea Debrut, Laetitia Jean, Sophie Bernard, Damien Genty, Rachid Zoubairi, Isabelle Remy-Jouet, Bernard Geny, Christian Boitard, Andrew Mammen, Alain Meyer, Olivier Boyer.

Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.

DOI: https://doi.org/10.1038/s41467-024-49460-1
Immunity. 2024 Jun 17. pii: S1074-7613(24)00279-6. [Epub ahead of print]

Cellular spermine targets JAK signaling to restrain cytokine-mediated autoimmunity.

Henan Xu, Xiao Zhang, Xin Wang, Bo Li, Hang Yu, Yuan Quan, Yan Jiang, Yuling You, Yan Wang, Mingyue Wen, Juan Liu, Min Wang, Bo Zhang, Yixian Li, Xuan Zhang, Qianjin Lu, Chu-Yi Yu, Xuetao Cao.

  Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.

Keywords:  JAK1; autoimmunity; autoinflammation; cytokine signaling; spermine; type I interferon

DOI:  https://doi.org/10.1016/j.immuni.2024.05.025
Cells. 2024 Jun 14. pii: 1036. [Epub ahead of print]13(12):

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.

Natalia F Zakirova, Olga A Khomich, Olga A Smirnova, Jennifer Molle, Sarah Duponchel, Dmitry V Yanvarev, Vladimir T Valuev-Elliston, Lea Monnier, Boyan Grigorov, Olga N Ivanova, Inna L Karpenko, Mikhail V Golikov, Cedric Bovet, Barbara Rindlisbacher, Alex R Khomutov, Sergey N Kochetkov, Birke Bartosch, Alexander V Ivanov.

  Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV's imprint on cell metabolism.

Keywords:  antiviral agents; hepatitis C virus; polyamines; proline metabolism; urea cycle

DOI:  https://doi.org/10.3390/cells13121036
Sci Adv. 2024 Jun 28. 10(26): eadn5228

Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis.

Shalil Khanal, Yuanhang Liu, Adebowale O Bamidele, Alexander Q Wixom, Alexander M Washington, Nidhi Jalan-Sakrikar, Shawna A Cooper, Ivan Vuckovic, Song Zhang, Jun Zhong, Kenneth L Johnson, M Cristine Charlesworth, Iljung Kim, Yubin Yeon, Sangwoong Yoon, Yung-Kyun Noh, Chady Meroueh, Abdul Aziz Timbilla, Usman Yaqoob, Jinhang Gao, Yohan Kim, Fabrice Lucien, Robert C Huebert, Nissim Hay, Michael Simons, Vijay H Shah, Enis Kostallari.

Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 (RAB31) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

DOI: https://doi.org/10.1126/sciadv.adn5228
Cell Mol Immunol. 2024 Jun 28.

Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma.

Yongchun Wang, Weibai Chen, Shuang Qiao, Hao Zou, Xing-Juan Yu, Yanyan Yang, Zhixiong Li, Junfeng Wang, Min-Shan Chen, Jing Xu, Limin Zheng.

  Metabolic changes play a crucial role in determining the status and function of macrophages, but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood. Here, we investigated the phenotype, contribution, and regulatory mechanisms of lipid droplet (LD)-laden macrophages (LLMs) in hepatocellular carcinoma (HCC). Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients. The LLMs displayed immunosuppressive phenotypes (with extensive expression of TREM2, PD-L1, CD206, and CD163) and attenuated the antitumor activities of CD8+ T cells. Mechanistically, tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages. LDs prolong LLM survival and promote CCL20 secretion, which further recruits CCR6+ Tregs to HCC tissue. Inhibiting LLM formation by targeting DGAT1 and DGAT2, which catalyze the synthesis of triglycerides, significantly reduced Treg recruitment, and delayed tumor growth in a mouse hepatic tumor model. Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

Keywords:  CCL20; Hepatocellular carcinoma; Lipid droplets; Macrophage survival; Treg

DOI:  https://doi.org/10.1038/s41423-024-01199-x