bims-imicid 2025-01-26 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–01–26
thirteen papers selected by
Dylan Ryan, University of Cambridge

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.
Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.
Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis.
Metabolic reprogramming of naïve regulatory T cells by IL-7 and IL-15 promotes their persistence and performance upon adoptive transfer.
Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism.
Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of Mycobacterium abscessus in macrophages.
Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.
Fiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection.
Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis.
Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism.
Ketogenesis nutritionally supports brain during bacterial infection in Drosophila.
Mannose: A game-changer for T cell immunotherapy.

Nat Cancer. 2025 Jan 17.

Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity.

Jiaxin Liang, Tevis Vitale, Xixi Zhang, Thomas D Jackson, Deyang Yu, Mark Jedrychowski, Steve P Gygi, Hans R Widlund, Kai W Wucherpfennig, Pere Puigserver.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

DOI: https://doi.org/10.1038/s43018-024-00895-x
Sci Adv. 2025 Jan 24. 11(4): eadu4369

Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.

Joshua S Stoolman, Rogan A Grant, Leah K Billingham, Taylor A Poor, Samuel E Weinberg, Madeline C Harding, Ziyan Lu, Jason Miska, Marten Szibor, Gr Scott Budinger, Navdeep S Chandel.

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.

DOI: https://doi.org/10.1126/sciadv.adu4369
Sci Adv. 2025 Jan 24. 11(4): eadq7307

Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion.

Alessia Zotta, Juliana Toller-Kawahisa, Eva M Palsson-McDermott, Shane M O'Carroll, Órlaith C Henry, Emily A Day, Anne F McGettrick, Ross W Ward, Dylan G Ryan, Mark A Watson, Martin D Brand, Marah C Runtsch, Kathrin Maitz, Anna Lueger, Julia Kargl, Jan L Miljkovic, Ed C Lavelle, Luke A J O'Neill.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.adq7307
Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2423114122

Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis.

Manisha Priya, Sonu Kumar Gupta, Anil Koundal, Srajan Kapoor, Snigdha Tiwari, Saqib Kidwai, Luiz Pedro Sorio de Carvalho, Krishan Gopal Thakur, Dinesh Mahajan, Deepak Sharma, Yashwant Kumar, Ramandeep Singh.

  Itaconate, an abundant metabolite produced by macrophages upon interferon-γ stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with Mycobacterium tuberculosis increases itaconate levels in lung tissues. We also show that exposure to itaconate inhibits M. tuberculosis growth in vitro, in macrophages, and mice. We report that exposure to sodium itaconate (ITA) interferes with the central carbon metabolism of M. tuberculosis. In addition to the inhibition of isocitrate lyase (ICL), we demonstrate that itaconate inhibits aldolase and inosine monophosphate (IMP) dehydrogenase in a concentration-dependent manner. Previous studies have shown that Rv2498c from M. tuberculosis is the bona fide (S)-citramalyl-CoA lyase, but the remaining components of the pathway remain elusive. Here, we report that Rv2503c and Rv3272 possess itaconate:succinyl-CoA transferase activity, and Rv2499c and Rv3389c possess itaconyl-CoA hydratase activity. Relative to the parental and complemented strains, the ΔRv3389c strain of M. tuberculosis was attenuated for growth in itaconate-containing medium, in macrophages, mice, and guinea pigs. The attenuated phenotype of ΔRv3389c strain of M. tuberculosis is associated with a defect in the itaconate dissimilation and propionyl-CoA detoxification pathway. This study thus reveals that multiple metabolic enzymes are targeted by itaconate in M. tuberculosis. Furthermore, we have assigned the two remaining enzymes responsible for the degradation of itaconic acid into pyruvate and acetyl-CoA. Finally, we also demonstrate the importance of enzymes involved in the itaconate dissimilation pathway for M. tuberculosis pathogenesis.

Keywords:  Mycobacterium tuberculosis; dissimilation; itaconate; pathogenesis

DOI:  https://doi.org/10.1073/pnas.2423114122
Commun Biol. 2025 Jan 21. 8(1): 99

Metabolic reprogramming of naïve regulatory T cells by IL-7 and IL-15 promotes their persistence and performance upon adoptive transfer.

Jessica Filoni, Arianna Ferrari, Tatiana Jofra, Anna Rita Putignano, Lorenzo Da Dalt, Susanna Cesarano, Carla Di Dedda, Fabrizia Bonacina, Federica Marchesi, Danilo Norata, Chiara Bonini, Lorenzo Piemonti, Paolo Monti.

Tregs for adoptive therapy are traditionally expanded ex vivo using high doses of IL-2. However, the final Treg product has limited survival once infused in patients, potentially affecting therapeutic effectiveness. Here, we tested a novel expansion protocol in which highly purified naïve Tregs were expanded with a combination of IL-7 and IL-15, in the absence of IL-2. The final Treg product was enriched with cells displaying an immature CD45RA+CD62L+CD95+ phenotype, reminiscent of conventional memory stem T cells. The combination of IL-7 and IL-15 confers Tregs a glycolytic metabolism and improved metabolic fitness, characterized by an increased capacity to adapt metabolism according to glucose and oxygen availability. Tregs expanded with IL-7 and IL-15 showed longer persistence and an improved capacity to control xeno-GvHD in NSG mice. This work suggests that metabolic reprogramming induced by IL-7 and IL-15 provides better Treg performance for adoptive therapy.

DOI: https://doi.org/10.1038/s42003-024-07381-1
Sci China Life Sci. 2025 Jan 13.

Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism.

Ziyi Han, Jian Fu, Aiyan Gong, Wenkai Ren.

  The gut microbiota plays key roles in host health by shaping the host immune responses through their metabolites, like indole derivatives from tryptophan. However, the direct role of these indole derivatives in macrophage fate decision and the underlying mechanism remains unknown. Here, we found that bacterial indole-3-propionic acid (IPA) downregulates interleukin-1beta (IL-1β) production in M1 macrophages through inhibition of nuclear factor-kappa B (NF-κB) signaling. Mechanistically, IPA binds specifically with methionine adenosyl-transferase 2A (MAT2A) to promote S-adenosylmethionine (SAM) synthesis, which facilitates the DNA methylation of ubiquitin-specific peptidase 16 (USP16, a deubiquitinase), and in turn promotes Toll-like receptor 4 (TLR4) ubiquitination and NF-κB inhibition. Furthermore, IPA administration attenuates sepsis in mouse models induced by lipopolysaccharides (LPS), showcasing its potential as a microbial-derived adjunct in alleviating inflammation. Collectively, our findings reveal a newly found microbial metabolite-immune system regulatory pathway mediated by IPA.

Keywords:  IL-1β; IPA; MAT2A; macrophage

DOI:  https://doi.org/10.1007/s11427-024-2789-1
Virulence. 2025 Dec;16(1): 2454323

Restriction of mitochondrial oxidation of glutamine or fatty acids enhances intracellular growth of Mycobacterium abscessus in macrophages.

Ho Won Kim, Ji Won Lee, Hoe Sun Yoon, Hwan-Woo Park, Young Ik Lee, Sung Ki Lee, Jake Whang, Jong-Seok Kim.

  Mycobacterium abscessus (Mab), a nontuberculous mycobacterium, is increasing in prevalence worldwide and causes treatment-refractory pulmonary diseases. However, how Mab rewires macrophage energy metabolism to facilitate its survival is poorly understood. We compared the metabolic profiles of murine bone marrow-derived macrophages (BMDMs) infected with smooth (S)- and rough (R)-type Mab using extracellular flux technology. Mab infection shifted BMDMs towards a more energetic phenotype, marked by increased oxidative phosphorylation (OXPHOS) and glycolysis, with a significantly greater enhancement in OXPHOS. This metabolic adaptation was characterized by enhanced ATP production rates, particularly in cells infected with S-type Mab, highlighting OXPHOS as a key energy source. Notably, Mab infection also modulated mitochondrial substrate preferences, increasing fatty acid oxidation capabilities while revealing significant changes in glutamine dependency and flexibility. R-type Mab infections exhibited a marked decrease in glutamine reliance but enhanced metabolic flexibility and capacity. Furthermore, targeting metabolic pathways related to glutamine and fatty acid oxidation exacerbated Mab growth within macrophages, suggesting these pathways play a protective role against infection. These insights advance our understanding of Mab's impact on host cell metabolism and propose a novel avenue for therapeutic intervention. By manipulating host mitochondrial metabolism, we identify a potential host-directed therapeutic strategy against Mab, offering a promising alternative to conventional treatments beleaguered by drug resistance. This study underscores the importance of exploring metabolic interventions to combat Mab infection, paving the way for innovative approaches in the fight against this formidable pathogen.

Keywords:  Mycobacterium abscessus; OXPHOS; glycolysis; metabolism

DOI:  https://doi.org/10.1080/21505594.2025.2454323
Sci Adv. 2025 Jan 24. 11(4): eadq9301

Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation.

Jing Wu, Komudi Singh, Vivian Shing, Anand Gupta, Brett C Arenberg, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.

Although lipid-derived acetyl-coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1-/- cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1-/- and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects' monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling.

DOI: https://doi.org/10.1126/sciadv.adq9301
Cell Host Microbe. 2025 Jan 11. pii: S1931-3128(24)00484-0. [Epub ahead of print]

Fiber- and acetate-mediated modulation of MHC-II expression on intestinal epithelium protects from Clostridioides difficile infection.

José L Fachi, Sarah de Oliveira, Tihana Trsan, Silvia Penati, Susan Gilfillan, Siyan Cao, Pollyana Ribeiro Castro, Mariane Font Fernandes, Krzysztof L Hyrc, Xiuli Liu, Patrick Fernandes Rodrigues, Bishan Bhattarai, Brian T Layden, Marco Aurélio R Vinolo, Marco Colonna.

  Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4+ intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate-induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4+ IELs.

Keywords:  Clostridioides difficile; MHC-II; diet; fibers; group 3 innate lymphoid cells; gut microbiota; interleukin-22; intestinal epithelial cells; intraepithelial lymphocytes; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.chom.2024.12.017
J Dermatol Sci. 2025 Jan 09. pii: S0923-1811(25)00002-7. [Epub ahead of print]

Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis.

Thomas Steadman, Steven O'Reilly.

   BACKGROUND: Systemic Sclerosis (SSc) is an idiopathic rheumatic inflammatory disease that is characterised by inflammation and skin fibrosis. Type I interferon is significantly elevated in the disease.
OBJECTIVE: The objective of this study is to determine the role of the TCA cycle metabolite fumarate in SSc.
METHODS: CD14 + cells were isolated from 12 SSc patients and healthy controls. Fumarate hydratase and Interferon dependant genes were quantified by qPCR. In vitro inhibition of STING using a small molecule STING inhibitor and enforced mitophagy was induced in vitro and IFN-β release was quantified. VDAC1 inhibitor was used to determine the role of mt DNA release in IFN-β induction. In whole skin biopsies fumarate and succinate was quantified.
RESULTS: Fumarate Hydratase is significantly reduced in SSc monocytes. Type I interferon is also elevated in monocytes from SSc donors compared to controls. The mitochondrial-specific stress marker GDF-15 was significantly elevated in SSc monocytes. Blockade of the cGAS-STING pathway chemically reduced interferon-β release and induced mitophagy also retarded release of the cytokine in response to LPS stimulation. Inhibition of VDAC1 mitigated IFN-β, as did the depletion of mitochondria in cells. Furthermore, the itaconate derivative 4-octyl itaconate reduced IFN-β induction in SSc monocytes, that was downstream of mitochondrial nucleic acid release. Fumarate, but not succinate was elevated in whole skin biopsies.
CONCLUSION: Fumarate metabolism links interferon release in SSc and may underlie the aberrant expression of interferon in SSc via cytosolic DNA released from mitochondria.

Keywords:  CGAS; DNA; Fibrosis; Fumarate hydratase; Interferon; STING; Systemic sclerosis

DOI:  https://doi.org/10.1016/j.jdermsci.2025.01.002
FEBS J. 2025 Jan 21.

Succinate receptor 1 signaling mutually depends on subcellular localization and cellular metabolism.

Aenne-Dorothea Liebing, Philipp Rabe, Petra Krumbholz, Christian Zieschang, Franziska Bischof, Angela Schulz, Susan Billig, Claudia Birkemeyer, Thanigaimalai Pillaiyar, Mikel Garcia-Marcos, Robert Kraft, Claudia Stäubert.

  Succinate is a pivotal tricarboxylic acid cycle metabolite but also specifically activates the Gi- and Gq-coupled succinate receptor 1 (SUCNR1). Contradictory roles of succinate and succinate-SUCNR1 signaling include reports about its anti- or pro-inflammatory effects. The link between cellular metabolism and localization-dependent SUCNR1 signaling qualifies as a potential cause for the reported conflicts. To systematically address this connection, we used a diverse set of methods, including several bioluminescence resonance energy transfer-based biosensors, dynamic mass redistribution measurements, second messenger and kinase phosphorylation assays, calcium imaging, and metabolic analyses. Different cellular metabolic states were mimicked using glucose (Glc) or glutamine (Gln) as available energy substrates to provoke differential endogenous succinate (SUC) production. We show that SUCNR1 signaling, localization, and metabolism are mutually dependent, with SUCNR1 showing distinct spatial and energy substrate-dependent Gi and Gq protein activation. We found that Gln-consumption associated with a higher rate of oxidative phosphorylation causes increased extracellular SUC concentrations, accompanied by a higher rate of SUCNR1 internalization, reduced miniGq protein recruitment to the plasma membrane, and lower Ca2+ signals. In Glc, under basal conditions, SUCNR1 causes stronger Gq than Gi protein activation, while the opposite is true upon stimulation with an agonist. In addition, SUCNR1 specifically interacts with miniG proteins in endosomal compartments. In THP-1 cells, polarized to M2-like macrophages, endogenous SUCNR1-mediated Gi signaling stimulates glycolysis, while Gq signaling inhibits the glycolytic rate. Our results suggest that the metabolic context determines spatially dependent SUCNR1 signaling, which in turn modulates cellular energy homeostasis and mediates adaptations to changes in SUC concentrations.

Keywords:  SUCNR1; macrophages; metabolism; signal transduction; succinate

DOI:  https://doi.org/10.1111/febs.17407
Brain Behav Immun. 2025 Jan 15. pii: S0889-1591(25)00017-0. [Epub ahead of print]125 280-291

Ketogenesis nutritionally supports brain during bacterial infection in Drosophila.

Gabriela Krejčová, Diana Novotná, Adam Bajgar.

  Mounting an immune response is a nutritionally demanding process that requires the systemic redistribution of energy stores towards the immune system. This is facilitated by cytokine-induced insulin resistance, which simultaneously promotes the mobilization of lipids and carbohydrates while limiting their consumption in immune-unrelated processes, such as development, growth, and reproduction. However, this adaptation also restricts the availability of nutrients to vital organs, which must then be sustained by alternative fuels. Here, we employed an experimental model of severe bacterial infection in Drosophila melanogaster to investigate whether ketogenesis may represent a metabolic adaptation for overcoming periods of nutritional scarcity during the immune response. We found that the immune response to severe bacterial infection is accompained by increased ketogenesis in the fat body and macrophages, leading to elevated levels of β-hydroxybutyrate in circulation. Although this metabolic adaptation is essential for survival during infection, it is not required for the elimination of the pathogen itself. Instead, ketone bodies predominately serve as an energy source for the brain neurons during this period of nutrient scarcity.

Keywords:  Adipocytes; Brain; Infection; Ketone bodies; Macrophages; Metabolism; Neurons; The fat body; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbi.2025.01.008
Cell Metab. 2025 Jan 15. pii: S1550-4131(24)00496-0. [Epub ahead of print]

Mannose: A game-changer for T cell immunotherapy.

Jingwei Ma, Shuai Tong, Jingxuan Xiao, Bo Huang.

Metabolism influences the behavior of various immune cell types. In a recent Cancer Cell study, Qiu et al. revealed mannose metabolism as a prominent metabolic feature of tumor precursor exhausted T cells (Tpex) that is crucial for maintaining T cell stemness. Their work uncovers a novel metabolic mechanism that decouples T cell proliferation from differentiation, providing valuable insights into how metabolic modulation can be used to generate "better" T cells during the manufacturing process.

DOI: https://doi.org/10.1016/j.cmet.2024.12.014