bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–01–12
ten papers selected by
Dylan Ryan, University of Cambridge
  1. Itaconate drives pro-inflammatory responses through proteasomal degradation of GLO1.
  2. [Progress in the immunometabolism in the regulation of macrophage function in sepsis].
  3. Pharmacological inhibition of key metabolic pathways attenuates Leishmania spp infection in macrophages.
  4. Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
  5. Research Progress on Glycolysis Mechanism of Psoriasis.
  6. Macrophage Immunometabolism - Emerging Targets for Regrowth in Aging Muscle.
  7. Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.
  8. Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
  9. Dendritic cell immunometabolism - a potential therapeutic target for allergic diseases.
  10. Infection-induced lysine lactylation enables herpesvirus immune evasion.
  1. Biochem Biophys Res Commun. 2025 Jan 06. pii: S0006-291X(25)00006-3. [Epub ahead of print]747 151292
    Itaconate drives pro-inflammatory responses through proteasomal degradation of GLO1.
    Lulu Bai, Hanghui Yu, Yiqing Cai, Runliu Wu, Rui Kang, Yuanyuan Jia, Xinyue Zhang, Daolin Tang, Enyong Dai.
      Itaconate is a small-molecule metabolite generated by the enzyme aconitate decarboxylase 1 (ACOD1), which is upregulated during inflammation. Traditionally, itaconate has been recognized for its anti-inflammatory properties; however, this study reveals a pro-inflammatory mechanism of itaconate in macrophages. We demonstrate that itaconate promotes the proteasomal degradation of glyoxalase 1 (GLO1) via Cys139. GLO1 is crucial for detoxifying methylglyoxal (MGO), a glycolysis byproduct that leads to advanced glycation end-products (AGEs). Elevated concentrations of itaconate correlate with reduced GLO1 expression in peripheral blood mononuclear cells (PBMCs) from patients with sepsis, linking increased itaconate concentrations to heightened MGO and AGE production. Functionally, itaconate-induced degradation of GLO1 promotes the accumulation of MGO and AGEs, thereby exacerbating inflammatory responses. In vivo, itaconate-treated myeloid-specific Ager conditional knockout mice exhibited reduced inflammation and improved survival in experimental sepsis models compared to wild-type controls. Collectively, these findings reveal a novel function of itaconate in immunometabolism, shedding light on its complex involvement in lethal infections.
    Keywords:  ACOD1; AGER; Degradation; GLO1; Inflammation; Macrophages; itaconate
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151292
  2. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2024 Dec;36(12): 1321-1324
    [Progress in the immunometabolism in the regulation of macrophage function in sepsis].
    Yingying Lu, Yan Bai, Fei Li, Zhuqing Rao.
      Macrophages are widely distributed in peripheral blood, lungs, liver, brain, kidneys, skin, testes, vascular endothelial cells, and other parts of the body. As sentinel cells of innate immunity, they play an important role in the occurrence and development of sepsis. Recent research in immune metabolism has revealed the complicated relationship between specific metabolic pathways of macrophages and their phenotype and function in sepsis. During the pro-inflammatory phase of sepsis, macrophages are characterized by glycolysis, while in the immunosuppressive phase, they rely more on mitochondrial oxidative phosphorylation (OXPHOS). Hence, this review describes how macrophages metabolism related signaling pathways, molecules, enzymes and metabolic intermediates determine their phenotype and function to find critical targets which regulate the body immune status in sepsis.
    DOI:  https://doi.org/10.3760/cma.j.cn121430-20231216-01089
  3. PLoS Negl Trop Dis. 2025 Jan 07. 19(1): e0012763
    Pharmacological inhibition of key metabolic pathways attenuates Leishmania spp infection in macrophages.
    Elaine Carvalho de Oliveira, Rafael Tibúrcio, Gabriela Duarte, Amanda Lago, Léon de Melo, Sara Nunes, Gustavo Gastão Davanzo, Ana Júlia Martins, Bruno Vinagre Ribeiro, Deborah Mothé, Juliana B P Menezes, Patrícia Veras, Natalia Tavares, Pedro M Moraes-Vieira, Cláudia Ida Brodskyn.
      Macrophages represent a fundamental component of the innate immune system that play a critical role in detecting and responding to pathogens as well as danger signals. Leishmania spp. infections lead to a notable alteration in macrophage metabolism, whereby infected cells display heightened energy metabolism that is linked to the integrity of host mitochondria. However, little is known about how different species of Leishmania manipulate host metabolism. Here, we demonstrate that despite differences in their mechanisms for evading host immune responses, L. amazonensis and L. braziliensis induce comparable disruptions in key metabolic pathways. We found that infected macrophages exhibited an overall elevation in energy metabolism regardless of the parasite strain, evidenced by the elevation in glycolysis and oxygen consumption rates, along with increased proton leak and decreased ATP production. We also analyzed the effects of both Leishmania spp. strain infection on mitochondria function, further revealing that infected cells display heightened mitochondrial mass and membrane potential. To investigate the metabolic pathways required for Leishmania amastigotes to persist in BMDMs, we pre-treated cells with small molecule drugs that target major metabolic pathways, revealing that perturbations in several metabolic processes affected parasite survival in a strain-independent manner. Treatments with inhibitors of the oxidative phosphorylation and glycolysis substantially reduced parasite loads. Collectively, our findings suggest that L.amazonensis and L.braziliensis exploit host cell metabolic pathways similarly to survive in macrophages.
    DOI:  https://doi.org/10.1371/journal.pntd.0012763
  4. Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01523-7. [Epub ahead of print]44(1): 115172
    Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine.
    Juliana Escher Toller-Kawahisa, Paula Ramos Viacava, Eva Margareta Palsson-McDermott, Daniele Carvalho Nascimento, Mariana Patricia Cervantes-Silva, Shane Myles O'Carroll, Alessia Zotta, Luis Eduardo Alves Damasceno, Gabriel Azevedo Públio, Pedro Forti, João Paulo Mesquita Luiz, Bruno Marcel Silva de Melo, Timna Varela Martins, Vitor Marcel Faça, Annie Curtis, Thiago Mattar Cunha, Fernando de Queiroz Cunha, Luke Anthony John O'Neill, José Carlos Alves-Filho.
      Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.
    Keywords:  CP: Immunology; CP: Metabolism; IL-10; PKM2; adenosine; macrophage; mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115172
  5. Psoriasis (Auckl). 2024 ;14 195-206
    Research Progress on Glycolysis Mechanism of Psoriasis.
    Lu Wei, Buxin Zhang, Yuanhui Tu, Aimin Liu.
      Psoriasis is a chronic inflammatory disease with a complex pathogenesis. Hyperplasia of glycolytic-dependent epidermal keratinocytes (KCs) is a new hallmark of psoriasis pathogenesis. Meanwhile, immune cells undergo metabolic reprogramming similar to KCs. Glycolysis provides energy for the proliferation of KCs, while it also releases lactic acid to facilitate the differentiation of immune cells. In turn, differentiated immune cells further promote KCs glycolysis by releasing inflammatory factors, thus forming an immunometabolism loop. The interaction between immune response and metabolic pathways jointly promotes the sustained proliferation of KCs and the secretion of various inflammatory factors by immune cells. Understanding the role of glycolysis in immunometabolism of psoriasis may provide new ideas for non-immunosuppressive treatment of psoriasis. This article aims to review the role of glycolysis in the pathogenesis of psoriasis and attempts to summarize the key enzymes and regulatory factors involved in psoriasis glycolysis, as well as their interactions. Finally, we discuss the pharmacological modulators of glycolysis in psoriasis.
    Keywords:  glycolysis; immunometabolism; keratinocytes; metabolic reprogramming; psoriasis
    DOI:  https://doi.org/10.2147/PTT.S493315
  6. Am J Physiol Endocrinol Metab. 2025 Jan 06.
    Macrophage Immunometabolism - Emerging Targets for Regrowth in Aging Muscle.
    Zachary J Fennel, Ryan M O'Connell, Micah J Drummond.
      The recovery from muscle atrophy is impaired with aging as characterized by improper muscle remodeling and sustained functional deficits. Age-related deficits in muscle regrowth are tightly linked with the loss of early pro-inflammatory macrophage responses and subsequent cellular dysregulation within the skeletal muscle niche. Macrophage inflammatory phenotype is regulated at the metabolic level, highlighting immunometabolism as an emerging strategy to enhance macrophage responses and restore functional muscle regrowth. Accordingly, metabolic targets with an emphasis on glycolytic, hypoxia, and redox-related pathways stand out for their role in promoting macrophage inflammation and enhancing muscle regrowth in aging. Here we highlight promising immuno-metabolic targets which could be leveraged to restore optimal pro-inflammatory macrophage function in aging and enhance muscle regrowth following muscular atrophy.
    Keywords:  aging; immune cells; inflammation; metabolism; muscle remodeling
    DOI:  https://doi.org/10.1152/ajpendo.00403.2024
  7. JCI Insight. 2025 Jan 07. pii: e186000. [Epub ahead of print]
    Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.
    Anil Kumar, Jugal Das, Hao-Yun Peng, Liqing Wang, Darby Ballard, Yijie Ren, Xiaofang Xiong, Xingcong Ren, Jin-Ming Yang, Paul de Figueiredo, Jianxun Song.
      The nucleus accumbens-associated protein-1 (NAC1) has recently emerged as a pivotal factor in oncogenesis by promoting glycolysis. Deletion of NAC1 in regulatory T cells (Tregs) has been shown to enhance FoxP3 stability, a suppressor of glycolysis. This study delves into the intriguing dual role of NAC1, uncovering that Tregs-specific deletion of NAC1 fosters metabolic fitness in Tregs, thereby promoting tumorigenesis. Our results unveil that NAC1-deficient Tregs exhibit prolonged survival and heightened function, particularly in acidic environments. Mechanistically, we find that NAC1-deficient Tregs adapt to adverse conditions by upregulating FoxP3 expression, engaging in CD36-mediated lipid metabolism, and enhancing PGC-1α-regulated mitochondrial function. In mouse tumor xenograft models, NAC1-deficient mice demonstrate increased susceptibility to tumor growth. Notably, Tregs lacking NAC1 not only display elevated lipid metabolism and mitochondrial fitness but also exhibit enhanced tumoral infiltration. Adoptive Treg transfer experiments further underscore the supportive role of NAC1-deficient Tregs in tumor growth. These findings suggest that modulating NAC1 expression in FoxP3+ Tregs could serve as a promising approach to augment antitumor immunity. Understanding the intricate interplay between NAC1 and Tregs opens avenues for potential therapeutic strategies targeting the tumor microenvironment (TME).
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1172/jci.insight.186000
  8. Sci Immunol. 2025 Jan 10. 10(103): eadl4909
    Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.
    Cody Elkins, Chengyu Ye, Pulavendran Sivasami, Roy Mulpur, Pamela P Diaz-Saldana, Amy Peng, Miaoer Xu, Yeun-Po Chiang, Samara Moll, Dormarie E Rivera-Rodriguez, Luisa Cervantes-Barragan, Tuoqi Wu, Byron B Au-Yeung, Christopher D Scharer, Mandy L Ford, Haydn Kissick, Chaoran Li.
      Regulatory T cells (Tregs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT Tregs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2hi VAT Treg subsets. Treg-specific deletion of Srebf2, the master regulator of cholesterol homeostasis, selectively reduced ST2hi VAT Tregs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2hi VAT Treg subsets after Srebf2 deletion. Srebf2-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2hi VAT Treg accumulation. However, long-term high-fat diet feeding disrupted VAT Treg cholesterol homeostasis and impaired clonal expansion of the ST2hi subset. Restoring Treg cholesterol homeostasis rescued VAT Treg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for Treg-targeted therapies in obesity-associated metabolic diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.adl4909
  9. Int J Med Sci. 2025 ;22(2): 417-431
    Dendritic cell immunometabolism - a potential therapeutic target for allergic diseases.
    Chuang Ouyang, Jiaying Huang, Gonghua Huang, Yanyan Wang.
      Allergic diseases are a group of chronic inflammatory disorders driven by abnormal immune responses. Dendritic cells (DCs) play a pivotal role in the initiation and progression of allergic diseases by modulating T cell responses. Extensive progress has been made in characterizing crucial roles of metabolic reprogramming in the regulation of immune cell functions. As the critical upstream regulators and effectors in allergic responses, the activation, migration, and function of DCs are reliant on metabolic reprogramming. In this review, we summarize the metabolic characteristics of DCs, and how the cellular microenvironment shapes DC function. We also elucidate the metabolic regulation of DC biology in the context of allergic diseases and targeted therapeutic strategies based on DC metabolism regulation. Understanding the functional alterations in DCs during allergic responses and the underlying mechanisms governing its metabolic regulation is crucial for the development of effective strategies for the prevention and treatment of allergic diseases.
    Keywords:  Allergic disease; Dendritic cell; Gut microbiota; Immunometabolism; T cell response; Targeted therapy
    DOI:  https://doi.org/10.7150/ijms.105532
  10. Sci Adv. 2025 Jan 10. 11(2): eads6215
    Infection-induced lysine lactylation enables herpesvirus immune evasion.
    Matthew D Tyl, Victoria U Merengwa, Ileana M Cristea.
      Aerobic glycolysis is a hallmark of many viral infections, leading to substantial accumulation of lactate. However, the regulatory roles of lactate during viral infections remain poorly understood. Here, we report that human cytomegalovirus (HCMV) infection leverages lactate to induce widespread protein lactylation and promote viral spread. We establish that lactyllysine is enriched in intrinsically disordered regions, regulating viral protein condensates and immune signaling transduction. Dynamic lactylation of immune factors suppresses immunity, a feature we show to be shared for HCMV and herpes simplex virus 1 infections, through regulation of RNA binding protein 14 and interferon-γ-inducible protein 16 (IFI16). K90 lactylation of the viral DNA sensor IFI16 inhibits recruitment of the DNA damage response kinase DNA-PK, preventing IFI16-driven virus gene repression and cytokine induction. Together, we characterize global protein lactylation dynamics during virus infection, finding that virus-induced lactate contributes to its immune evasion through direct inhibition of immune signaling pathways.
    DOI:  https://doi.org/10.1126/sciadv.ads6215
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