bims-imicid 2025-02-02 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–02–02
thirty-six papers selected by
Dylan Ryan, University of Cambridge

Metabolic reprogramming in inflammaging and aging in T cells.
The cell autonomous and non-autonomous roles of itaconate in immune response.
Role of Glycolysis and Nitric Oxide Pathway Crosstalk in Macrophages in Atherosclerosis.
Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.
Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction.
Metabolomic analysis of murine tissues infected with Brucella melitensis.
MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma.
Ignoring Gender-Based Immunometabolic Reprograming, a Risky Business in Immune-Based Precision Medicine.
Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide.
Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.
Iron improves the antiviral activity of NK cells.
Glycolysis in asthma: Its role and potential as a diagnostic or therapeutic target.
Arginine metabolism in myeloid cells in health and disease.
Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.
Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses.
ASFV infection induces lipid metabolic disturbances and promotes viral replication.
tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.
Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.
Optical metabolic imaging identifies metabolic shifts and mitochondria heterogeneity in POLG mutator macrophages.
Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.
A metabolic conspiracy drives anti-tumorigenic macrophages.
Arginase-1-specific T cells target and modulate tumor-associated macrophages.
PFKFB3 decreases α-ketoglutarate production while partial PFKFB3 knockdown in macrophages ameliorates arthritis in tumor necrosis factor-transgenic mice.
Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.
A review collection on immunometabolism.
Label-free Detection and Characterization of Metabolism in Fresh and Cryopreserved Macrophages.
Cholesterol metabolism regulator SREBP2 inhibits HBV replication via suppression of HBx nuclear translocation.
Dengue virus is particularly sensitive to interference with long-chain fatty acid elongation and desaturation.
Gut microbe-derived betulinic acid alleviates sepsis-induced acute liver injury by inhibiting macrophage NLRP3 inflammasome in mice.
HBV and HBsAg strongly reshape the phenotype, function, and metabolism of DCs according to patients' clinical stage.
Hyperglycemic milieu impairs Vγ9Vδ2 T cell functions in tuberculosis patients and prolongs M.tb negative conversion time.
Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.
Metabolic profiles of cutaneous lupus have abnormalities in the nicotinamide adenine dinucleotide pathway.
The absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy-induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation.
Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets.

Life Metab. 2023 Oct;2(5): load028

Metabolic reprogramming in inflammaging and aging in T cells.

Alessio Bevilacqua, Ping-Chih Ho, Fabien Franco.

  Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.

Keywords:  T cells; immunometabolism; inflammaging

DOI:  https://doi.org/10.1093/lifemeta/load028
Cell Insight. 2025 Feb;4(1): 100224

The cell autonomous and non-autonomous roles of itaconate in immune response.

Chao Chen, Xinjian Li.

  Itaconate which is discovered as a mammalian metabolite possessing antimicrobial and immunoregulatory activity has attracted much attention in the field of immunometabolism. Itaconate is synthesized by myeloid cells under conditions of pathogen infection and sterile inflammation. In addition to regulating immune response of myeloid cells, itaconate secreted from myeloid cells can also be taken up by non-myeloid cells to exert immunoregulatory effects in a cell non-autonomous manner. In this review, we recap the discovery of itaconate as a distinct immunologic regulator and effector, describe the development of itaconate biosensor, and detail the recent findings that decipher the mechanism underlying intercellular transport of itaconate. Based on these knowledges, we propose itaconate is a messenger transmitting immunologic signals from myeloid cells to other types of cells during host inflammation and immune defense.

Keywords:  IRG1; Immunometabolism; Immunotransmitter; Inflammation; Innate immunity; Itaconate

DOI:  https://doi.org/10.1016/j.cellin.2024.100224
Curr Med Chem. 2025 Jan 24.

Role of Glycolysis and Nitric Oxide Pathway Crosstalk in Macrophages in Atherosclerosis.

Stanislav Kotlyarov.

  Atherosclerosis is a complex multifactorial process that occurs in the vascular wall over many years and is responsible for a number of major diseases that affect quality of life and prognosis. A growing body of evidence supports the notion that immune mechanisms underlie atherogenesis. Macrophages are considered one of the key participants in atherogenesis, but their role in this process is multifaceted, which is largely due to the peculiarities of their cellular metabolism. Glycolysis is not only an important metabolic pathway in macrophages, but is also associated with their immune functions. Glycolysis in macrophages has complex regulatory pathways and is cross-linked with nitric oxide, which together determine the immune function of these cells. Thus, the immune and metabolic links underlying atherogenesis are of research and clinical interest in terms of their potential therapeutic opportunities.

Keywords:  Atherosclerosis; glycolysis; immunometabolism; innate immune system; macrophages; nitric oxide.

DOI:  https://doi.org/10.2174/0109298673339364241224102645
Cell Metab. 2025 Jan 24. pii: S1550-4131(24)00489-3. [Epub ahead of print]

Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy.

Andrew T Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B Rhodes Ford, Supriya Joshi, Katarzyna M Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A Jana, Victoria G Dean, William G Gunn, Stacy Gelhaus, Amanda C Poholek, Dayana B Rivadeneira, Greg M Delgoffe.

  Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical in vitro expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding in vivo. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.

Keywords:  CAR-T; Immunometabolism; T cell; cell therapy; epigenetics; glucose; immunotherapy; longevity; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2024.12.007
Life Med. 2023 Jun;2(3): lnad021

Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction.

Jialin Ye, Jiemeng Fu, Hui Hou, Yan Wang, Wei Deng, Shumeng Hao, Yifei Pei, Jing Xu, Mingyue Zheng, Yichuan Xiao.

  DNA accumulation is associated with the development of autoimmune inflammatory diseases. However, the pathological role and underlying mechanism of cytoplasmic DNA accumulation in CD4+ T cells have not been well established. Here, we show that Trex1 deficiency-induced endogenous DNA accumulation in CD4+ T cells greatly promoted their induction of autoimmune inflammation in a lupus-like mouse model. Mechanistically, the accumulated DNA in CD4+ T cells was sensed by the KU complex, then triggered the activation of DNA-PKcs and ZAK and further facilitated the activation of AKT, which exacerbated glycolysis, thereby promoting the inflammatory responses. Accordingly, blocking the DNA sensing pathway in CD4+ T cells by genetic knockout of Zak or using our newly developed ZAK inhibitor iZAK2 attenuated all pathogenic characteristics in a lupus-like inflammation mouse model induced with Trex1-deficient CD4+ T cells. Overall, our study demonstrated a causal link between DNA-sensing and metabolic reprogramming in CD4+ T cells for inflammatory induction and suggested inhibition of the DNA sensing pathway may be a potential therapy for the treatment of inflammatory diseases.

Keywords:  CD4+ T; DNA sensing; autoimmunity disease; glycolysis; inflammation

DOI:  https://doi.org/10.1093/lifemedi/lnad021
PLoS One. 2025 ;20(1): e0314672

Metabolomic analysis of murine tissues infected with Brucella melitensis.

Bárbara Ponzilacqua-Silva, Alexis S Dadelahi, Charles R Moley, Mostafa F N Abushahba, Jerod A Skyberg.

Brucella is a gram negative, facultative intracellular bacterial pathogen that constitutes a substantial threat to human and animal health. Brucella can replicate in a variety of tissues and can induce immune responses that alter host metabolite availability. Here, mice were infected with B. melitensis and murine spleens, livers, and female reproductive tracts were analyzed by GC-MS to determine tissue-specific metabolic changes at one-, two- and four- weeks post infection. The most remarkable changes were observed at two-weeks post-infection when relative to uninfected tissues, 42 of 329 detected metabolites in reproductive tracts were significantly altered by Brucella infection, while in spleens and livers, 68/205 and 139/330 metabolites were significantly changed, respectively. Several of the altered metabolites in host tissues were linked to the GABA shunt and glutaminolysis. Treatment of macrophages with GABA did not alter control of B. melitensis infection, and deletion of the putative GABA transporter BMEI0265 did not alter B. melitensis virulence. While glutaminolysis inhibition did not affect control of B. melitensis in macrophages, glutaminolysis was required for macrophage IL-1β production in response to B. melitensis. In summary, these results indicate that Brucella infection alters host tissue metabolism and that these changes could have effects on inflammation and the outcome of infection.

DOI: https://doi.org/10.1371/journal.pone.0314672
Nat Commun. 2025 Jan 27. 16(1): 1083

MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma.

Camille Niveau, Mélanie Cettour-Cave, Stéphane Mouret, Eleonora Sosa Cuevas, Mylene Pezet, Benoît Roubinet, Hugo Gil, Florence De Fraipont, Ludovic Landemarre, Julie Charles, Philippe Saas, Caroline Aspord.

Dendritic cells (DC) are key players in antitumor immune responses. Tumors exploit their plasticity to escape immune control; their aberrant surface carbohydrate patterns (e.g., glycans) shape immune responses through lectin binding, and manipulate the metabolism of immune cells, including DCs to alter their function and escape immune surveillance. DC metabolic reprogramming could induce immune subversion and tumor immune escape. Here we explore metabolic features of human DC subsets (cDC2s, cDC1s, pDCs) in melanoma, at single cell level, using the flow cytometry-based SCENITH (Single-Cell ENergetIc metabolism by profiling Translation inHibition) method. We demonstrate that circulating and tumor-infiltrating DC subsets from melanoma patients are characterized by altered metabolism, which is linked to their activation status and profile of immune checkpoint expression. This altered metabolism influences their function and affects patient clinical outcome. Notably, melanoma tumor cells directly remodel the metabolic profile of DC subsets, in a glycan-dependent manner. Strikingly, modulation of the mTOR/AMPK-dependent metabolic pathways and/or the MCT1 lactate transporter rescue cDC2s and cDC1s from skewing by tumor-derived glycans, Sialyl-Tn antigen and Fucose, and restore anti-tumor T-cell fitness. Our findings thus open the way for appropriate tuning of metabolic pathways to rescue DCs from tumor hijacking and restore potent antitumor responses.

DOI: https://doi.org/10.1038/s41467-025-56392-x
Front Biosci (Landmark Ed). 2025 Jan 09. 30(1): 27118

Ignoring Gender-Based Immunometabolic Reprograming, a Risky Business in Immune-Based Precision Medicine.

Vijay Kumar.

  Immunology advances have increased our understanding of autoimmune, auto-inflammatory, immunodeficiency, infectious, and other immune-mediated inflammatory diseases (IMIDs). Furthermore, evidence is growing for the immune involvement in aging, metabolic and neurodegenerative diseases, and different cancers. However, further research has indicated sex/gender-based immune differences, which further increase higher incidences of various autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE), myasthenia gravis, and rheumatoid arthritis (RA) in females. On the other hand, reproductive-age females also show a more potent immune response against infections and vaccines than their age-matched males-furthermore, some immune-based therapies, including immune checkpoint inhibitors (ICIs), show gender-based efficacy and adverse events. Metabolic demands are different in males and females. Immune cell function and polarization are also governed by their metabolic reprogramming, called immunometabolism and immunometabolic reprogramming (IR). Therefore, sex/gender-associated immune differences and their involvement in immune-mediated diseases and immune-based therapeutics indicate the demand for gender-based IR studies to increase the efficacy of immune-based precision medicine.

Keywords:  PRRs; immune cells; immunometabolic reprograming; immunometabolism; sex/gender

DOI:  https://doi.org/10.31083/FBL27118
Biofactors. 2025 Jan-Feb;51(1):51(1): e2149

Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide.

Katarina Milosevic, Ana Milosevic, Ivana Stevanovic, Anica Zivkovic, Danijela Laketa, Marija M Janjic, Ivana Bjelobaba, Irena Lavrnja, Danijela Savic.

  Modulating metabolic pathways in activated microglia can alter their phenotype, which is relevant in uncontrolled neuroinflammation as a component of various neurodegenerative diseases. Here, we investigated how pretreatment with agmatine, an endogenous polyamine, affects metabolic changes in an in vitro model of neuroinflammation, a murine microglial BV-2 cell line exposed to lipopolysaccharide (LPS). Hence, we analyzed gene expression using qPCR and protein levels using Western blot and ELISA. Microglial metabolic status was assessed by measuring lactate release and cellular ATP by enzymatic and luminescence spectrophotometry. Mitochondrial functionality was analyzed by fluorescent probes detecting mitochondrial membrane potential (mtMP) and superoxide production. Our findings suggest that kinase pathways associated with hypoxia-inducible factor-1α (HIF-1α) regulate energy metabolism in pro-inflammatory activated microglia. We have shown that LPS induces HIF-1α and genes for glucose transporter and glycolytic rate, increases lactate production and causes mitochondrial dysfunction, suggesting a metabolic shift towards glycolysis. Agmatine inhibits the PI3K/Akt pathway and negatively regulates mammalian target of rapamycin (mTOR) phosphorylation and HIF-1α levels, reducing lactate and tumor necrosis factor (TNF) production, which is supported by pharmacological blockade of PI3K. Pretreatment with agmatine also rescues mitochondrial function by counteracting the LPS-induced decline in mtMP and increase in mitochondrial superoxide, resulting in an anti-apoptotic effect. Agmatine alone increases intracellular ATP levels and maintains this effect even under pro-inflammatory conditions. Our study emphasizes the ability of agmatine to engage in metabolic reprogramming of pro-inflammatory microglia through increased ATP production and modulation of signaling pathway involved in promoting glycolysis and cytokine release.

Keywords:  ATP; HIF‐1α; PI3K/Akt/mTOR; agmatine; glycolysis; microglia

DOI:  https://doi.org/10.1002/biof.2149
Sci Adv. 2025 Jan 31. 11(5): eadr8837

Epstein-Barr virus-driven cardiolipin synthesis sustains metabolic remodeling during B cell transformation.

Haixi You, Larissa Havey, Zhixuan Li, Yin Wang, John M Asara, Rui Guo.

The Epstein-Barr virus (EBV) infects nearly 90% of adults globally and is linked to over 200,000 annual cancer cases. Immunocompromised individuals from conditions such as primary immune disorders, HIV, or posttransplant immunosuppressive therapies are particularly vulnerable because of EBV's transformative capability. EBV remodels B cell metabolism to support energy, biosynthetic precursors, and redox equivalents necessary for transformation. Most EBV-driven metabolic pathways center on mitochondria. However, how EBV regulates B cell mitochondrial function and metabolic fluxes remains unclear. Here, we show that EBV boosts cardiolipin (CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBV nuclear antigen 2/MYC-induced CL enzyme transactivation. Pharmacological and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis. Disrupting CL biosynthesis destabilizes mitochondrial matrix enzymes pivotal to these pathways. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering synthetic lethal strategies against EBV-associated B cell malignancies.

DOI: https://doi.org/10.1126/sciadv.adr8837
Front Immunol. 2024 ;15 1526197

Iron improves the antiviral activity of NK cells.

Simone Schimmer, Vaasudevan Sridhar, Zelal Satan, Anton Grebe, Mohamed Saad, Bernd Wagner, Nele Kahlert, Tanja Werner, Dana Richter, Ulf Dittmer, Kathrin Sutter, Elisabeth Littwitz-Salomon.

  Natural killer (NK) cells are innate immune cells that play a crucial role as a first line of defense against viral infections and tumor development. Iron is an essential nutrient for immune cells, but it can also pose biochemical risks such as the production of reactive oxygen species. The importance of iron for the NK cell function has gained increasing recognition. We have previously shown that NK cells require iron to efficiently eliminate virus-infected target cells; however, the impact of nutritional iron deficiency on NK cell function and the therapeutic benefits of iron supplementation remain unclear. Here, we demonstrate that diet-related low iron levels lead to increased retroviral loads due to functional NK cell impairment, while iron supplementation enhances NK cell proliferation, as well as their cytotoxic efficacy. Notably, iron-treated NK cells exhibited significant metabolic changes, including mitochondrial reorganization. Interestingly, although iron supplementation decreased the NK cell's cytokine production, it significantly improved NK cell degranulation and the expression of cytotoxicity-associated proteins. These findings highlight the critical role of iron in maintaining NK cell immunity and suggest that iron supplementation may hold therapeutic potential for supporting the treatment of viral infections and immunodeficiency disorders.

Keywords:  antiviral function; immunometabolism; iron metabolism; iron supplementation; natural killer cells; viral infection

DOI:  https://doi.org/10.3389/fimmu.2024.1526197
Int Immunopharmacol. 2025 Jan 27. pii: S1567-5769(25)00132-8. [Epub ahead of print]148 114143

Glycolysis in asthma: Its role and potential as a diagnostic or therapeutic target.

Xuejiao Lv, Wenrui Wang, Hongna Dong, Wei Li.

  Asthma is a heterogeneous disease characterized by chronic airway inflammation and hyperresponsiveness. A number of immune cells are involved in asthma pathogenesis, such as eosinophils, mast cells, T lymphocytes and neutrophils, as well as airway epithelial cells. Glycolysis plays a crucial role in glucose metabolism, and serves as a bridge between metabolic and inflammatory dysfunction. Research has found that abnormal glycolytic metabolism in various immune cells may contribute to the pathogenesis of asthma by inducing dysregulation in congenital and adaptive immune responses. Therefore, the inhibition of glycolysis can be a viable approach to prevent airway inflammation in asthma. The present study reviews the relationship between glycolysis and inflammatory cells in different asthma subtypes, and its potential therapeutic significance.

Keywords:  Asthma; Cell; Glycolysis; Subtype; Therapy

DOI:  https://doi.org/10.1016/j.intimp.2025.114143
Semin Immunopathol. 2025 Jan 25. 47(1): 11

Arginine metabolism in myeloid cells in health and disease.

Eleftheria Karadima, Triantafyllos Chavakis, Vasileia Ismini Alexaki.

  Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.

Keywords:  Arginine metabolism; Cancer; Infection; Inflammation; Myeloid cells; Sepsis-induced immune paralysis; Surgery

DOI:  https://doi.org/10.1007/s00281-025-01038-9
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564241312807

Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.

Elisa Navarro, Jorge Montesinos.

  Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining tissue homeostasis by monitoring and responding to environmental changes through processes such as phagocytosis, cytokine production or synapse remodeling. Their dynamic nature and diverse functions are supported by the regulation of multiple metabolic pathways, enabling microglia to efficiently adapt to fluctuating signals. A key aspect of this regulation occurs at mitochondria-associated ER membranes (MAM), specialized contact sites between the ER and mitochondria. These structures facilitate the exchange of calcium, lipids, and metabolites and serve as metabolic and signaling hubs. This review synthesizes current research on how MAM influence microglial physiology, with an emphasis on their role in immunometabolism, offering new insights into the integration of metabolic and immune functions in the CNS and its impact in the context of neurodegeneration.

Keywords:  ER-mitochondria contact sites; inflammation; metabolism; microglia; mitochondria-associated ER membranes (MAM); neurodegeneration

DOI:  https://doi.org/10.1177/25152564241312807
Cell Death Dis. 2025 Jan 25. 16(1): 41

Positive feedback loop involving AMPK and CLYBL acetylation links metabolic rewiring and inflammatory responses.

Wenke Wang, Boquan Wu, Mingjun Hao, Sichong Chen, Ruiting Cong, Wenjie Wu, Pengbo Wang, Qiaoyi Zhang, Pengyu Jia, Yuequn Song, Bo Liu, Siyao Qu, Jian-Fei Pei, Da Li, Naijin Zhang.

Metabolic rewiring underlies effective macrophages defense to respond disease microenvironment. However, the underlying mechanisms driving metabolic rewiring to enhance macrophage effector functions remain unclear. Here, we demonstrated that the metabolic reprogramming in inflammatory macrophages depended on the acetylation of CLYBL, a citramalyl-CoA lyase, at lysine 154 (K154), and blocking CLYBL-K154 acetylation restricted the release of pro-inflammatory factors. Mechanistically, we found a crucial AMPK-CLYBL acetylation positive feedback loop, triggered by toll-like receptors (TLRs), involving AMPK hypophosphorylation and CLYBL hyperacetylation. The deacetylase enzyme SIRT2 acted as the bridge between AMPK phosphorylation and CLYBL acetylation, thereby regulating macrophage polarization and the release of pro-inflammatory cytokines. Furthermore, CLYBL hypoacetylation decreased monocyte infiltration, thereby alleviating cardiac remodeling. These findings suggest that the AMPK-CLYBL acetylation positive feedback loop serves as a metabolic switch driving inflammatory response and inhibiting CLYBL-K154 acetylation may offer a promising therapeutic strategy for inflammatory response-related disorders.

DOI: https://doi.org/10.1038/s41419-025-07362-0
Front Microbiol. 2024 ;15 1532678

ASFV infection induces lipid metabolic disturbances and promotes viral replication.

Xuefei Chu, Shengqiang Ge, Yingchao Li, Qin Zhang, Xinyu Cui, Yuanyuan Zuo, Ruihong Li, Hongtao Sun, Lei Yin, Zhenzhong Wang, Jinming Li, Yihong Xiao, Zhiliang Wang.

   Introduction: African swine fever is a highly transmissible and lethal infectious disease caused by the African swine fever virus (ASFV), which has considerably impacted the global swine industry. Lipid metabolism plays a vital role in sustaining lipid and energy homeostasis within cells and influences the viral life cycle.
Methods and results: In this study, we found that ASFV infection disrupts lipid metabolism in the host. Transcriptomic analysis of cells infected with ASFV revealed that the levels of lipid metabolism significantly changed as the duration of the infection progressed. The intracellular cholesterol levels of the host exhibited a pattern similar to the viral growth curve during the course of infection. Notably, increased cholesterol levels promoted ASFV replication in host cells, whereas inhibition of the cholesterol biosynthesis pathway markedly reduced intracellular ASFV replication.
Discussion: The findings of this study showed that ASFV led to lipid metabolism disturbances to facilitate its replication, which is useful for revealing the mechanism underlying ASFV infection.

Keywords:  African swine fever virus; cholesterol; lipid metabolism; lipid synthesis; transcriptomic analysis

DOI:  https://doi.org/10.3389/fmicb.2024.1532678
J Exp Med. 2025 Mar 03. pii: e20240559. [Epub ahead of print]222(3):

tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.

Shan Miao, Hao Li, Xiaohan Song, Yongbo Liu, Gaoyang Wang, Chen Kan, Youqiong Ye, Ru-Juan Liu, Hua-Bing Li.

Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of effector functions. However, the posttranscriptional mechanisms underpinning this process remain obscure. The transfer RNA (tRNA) N1-methyladenine (m1A) modification, essential for tRNA stability and protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A "writer" gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase, a key enzyme for cholesterol biosynthesis. Cholesterol supplementation rescues the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings highlight tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20240559
bioRxiv. 2025 Jan 18. pii: 2025.01.14.632838. [Epub ahead of print]

Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.

Juan Marcos Oviedo, Diana Cortes-Selva, Marco Marchetti, Lauren Gordon, Lisa Gibbs, J Alan Maschek, James Cox, Seth Frietze, Eyal Amiel, Keke C Fairfax.

  We have previously identified that S. mansoni infection induces a unique form of myeloid training that protects male but not female mice from high fat diet induced disease. Here we demonstrate that ovarian derived hormones account for this sex specific difference. Ovariectomy of females prior to infection permits metabolic reprogramming of the myeloid lineage, with BMDM exhibiting carbon source flexibility for cellular respiration, and mice protected from systemic metabolic disease. The innate training phenotype of infection can be replicated by in vivo injection of SEA, and by exposure of bone marrow to SEA in culture prior to macrophage differentiation (Day 0). This protective phenotype is linked to increased chromatin accessibility of lipid and mitochondrial pathways in BMDM including Nrf1 and Tfam, as well as mitochondrial biogenesis. This work provides evidence that S. mansoni antigens induce a unique form of innate training inhibited by ovarian-derived hormones in females.

Keywords:  Myeloid lineage; Schistosoma mansoni; biological sex; innate training; macrophage metabolism; metabolic disease

DOI:  https://doi.org/10.1101/2025.01.14.632838
bioRxiv. 2025 Jan 15. pii: 2025.01.13.632822. [Epub ahead of print]

Optical metabolic imaging identifies metabolic shifts and mitochondria heterogeneity in POLG mutator macrophages.

Linghao Hu, A Phillip West, Alex J Walsh.

The polymerase gamma (POLG) gene mutation is associated with mitochondria and metabolism disorders, resulting in heterogeneous responses to immunological activation and posing challenges for mitochondrial disease therapy. Optical metabolic imaging captures the autofluorescent signal of two coenzymes, NADH and FAD, and offers a label-free approach to detect cellular metabolic phenotypes, track mitochondria morphology, and quantify metabolic heterogeneity. In this study, fluorescence lifetime imaging (FLIM) of NAD(P)H and FAD revealed that POLG mutator macrophages exhibit a decreased NAD(P)H lifetime, and optical redox ratio compared to the wild-type macrophages, indicating an increased dependence on glycolysis. FLIM revealed that both wild-type and POLG mutator macrophages switch to a decreased NAD(P)H τ 1 , and τ m after immune stimulation by Lipopolysaccharides (LPS). Furthermore, a bimodality index of subpopulation analysis identified heterogenous populations of POLG mutator macrophage responses under immune challenge by LPS. Moreover, to quantify the mitochondria variations in POLG mutator macrophages, a customized thresholding image processing pipeline was developed to segment mitochondria regions within each cell from the NADH image, allowing for the feature analysis of mitochondria clusters. Consequently, the wild-type macrophages exhibited a higher percentage of mitochondria-containing pixels and longer lengths of connected mitochondria, as compared with POLG mutated macrophages. Altogether, these results illustrate the potential of optical metabolic imaging for non-invasive detection and quantification of cellular metabolism, metabolic heterogeneity within cell populations, and intra-cellular mitochondria morphology differences in POLG mutator macrophages. Optical metabolic imaging will be valuable for studying POLG-mutation diseases and evaluating efficacy of potential therapies.

DOI: https://doi.org/10.1101/2025.01.13.632822
Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00030-8. [Epub ahead of print]612 217466

Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.

Shiyun Huang, Jiahao Shi, Jianfeng Shen, Xianqun Fan.

  Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.

Keywords:  Metabolism; Neutrophil; Therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217466
Life Metab. 2023 Apr;2(2): load009

A metabolic conspiracy drives anti-tumorigenic macrophages.

Na Li, Tiffany Horng.

DOI: https://doi.org/10.1093/lifemeta/load009
J Immunother Cancer. 2025 Jan 29. pii: e009930. [Epub ahead of print]13(1):

Arginase-1-specific T cells target and modulate tumor-associated macrophages.

Evelina Martinenaite, Inés Lecoq, Mia Aaboe-Jørgensen, Shamaila Munir Ahmad, Maria Perez-Penco, Hannah Jorinde Glöckner, Marion Chapellier, Lucía Lara de la Torre, Lars Rønn Olsen, Anne Mette Askehøj Rømer, Ayako Wakatsuki Pedersen, Mads Hald Andersen.

   BACKGROUND: Arginase-1 (Arg1) expressing tumor-associated macrophages (TAMs) may create an immune-suppressive tumor microenvironment (TME), which is a significant challenge for cancer immunotherapy. We previously reported the existence of Arg1-specific memory T cells among peripheral blood mononuclear cells (PBMCs) and described that Arg-1-based immune modulatory vaccines (IMVs) control tumor growth and alter the M1/M2 macrophage ratio in murine models of cancer. In the present study, we investigated how Arg1-specific T cells can directly target TAMs and influence their polarization.
METHODS: Murine Arg1-specific CD4+T cells isolated from splenocytes of animals vaccinated with an Arg1-derived peptide in the adjuvant montanide were co-cultured with either in vitro M2-differentiated bone marrow-derived macrophages or ex vivo isolated F4/80+TAMs. Human Arg1-specific CD4+T cell clones were co-cultured with Arg1-expressing TAMs generated in vitro from either PBMC-derived CD14+cells or the myeloid cell lines MonoMac1 and THP-1. MHC class II-restricted Arg-1 peptide presentation by macrophages was confirmed by immunopeptidomics. T-cell-mediated changes in the macrophage immune phenotype and cytokine microenvironment were examined using flow cytometry, RT-qPCR and multiplex immunoassay. The effect of Arg1-derived peptide IMV on TAMs in vivo was assessed by multiplex gene analysis of F4/80+cells.
RESULTS: We show that Arg1-based IMV-mediated tumor control was linked to a decrease in multiple immunosuppressive pathways in the TAM population of the treated animals. Tumor-conditioned media (TCM) derived from Arg1-vaccinated mice induced significantly higher upregulation of MHC-II on exposed myeloid cells compared with controls. Furthermore, murine CD4+Arg1-specific T cells were able to target TAMs and effectively reprogram their phenotype ex vivo by secreting IL2 and IFNγ. Next, we established that human Arg1+TAMs present Arg1-derived peptides and are directly recognized by proinflammatory CD4+Arg1-specific T cell clones. These CD4+Arg1-specific T cells were able to reprogram TCM-conditioned macrophages as observed by increased expression of CD80 and HLA-DR.
CONCLUSIONS: TAMs may be directly targeted and modulated by Arg1-specific CD4+T cells. These findings provide a strong rationale for future clinical development of Arg1-based IMVs to alter the immune-suppressive TME by reprogramming TAMs and promoting a proinflammatory TME.

Keywords:  Immune modulatory; Macrophage; T cell; Vaccine

DOI:  https://doi.org/10.1136/jitc-2024-009930
Int Immunopharmacol. 2025 Jan 26. pii: S1567-5769(25)00091-8. [Epub ahead of print]148 114102

PFKFB3 decreases α-ketoglutarate production while partial PFKFB3 knockdown in macrophages ameliorates arthritis in tumor necrosis factor-transgenic mice.

Xiaodong Zhu, Xiaohui Zhou, Shuaiyi Li, Zenghui Liu, Shidi Yu, Hong Shi, LingLing Zhu, Baohui Song, Zihou Si, Mingshuang Sun, Wei Zhu.

   OBJECTIVE: Aberrant 6-phosphofructo-2kinase/fructose-2,6-bisphoshatase 3 (PFKFB3) expression is tightly correlated with multiple steps of tumorigenesis; however, the pathological significance of PFKFB3 in macrophages in patients with rheumatoid arthritis (RA) remains obscure. In this study, we examined whether PFKFB3 modulates macrophage activation and promotes RA development.
METHOD: Peripheral blood mononuclear cells (PBMCs) from patients with RA, THP-1 cells, and bone marrow-derived macrophages from conditional PFKFB3-knockout mice were used to investigate the mechanism underlying PFKFB3-induced macrophage regulation of RA.
RESULT: We demonstrated that patients with RA have higher PFKFB3 levels than healthy volunteers. PFKFB3 silencing suppressed M1 macrophage polarization and downregulated IL-1β, CD80, IFIT1, CCL8, and CXCL10 in macrophages of patients with RA. PFKFB3 overexpression markedly upregulated IRF5, HIF1α, IL-1β, CD80, IFI27, IFI44, IFIT1, IFIT3, CCL2, CCL8, CXCL10, CXCL11, and MMP13 in phorbol 12-myristate 13-acetate-induced THP-1 cells, although these changes were partially reversed by PFK15, an inhibitor of PFKFB3 enzyme activity. Co-immunoprecipitation assays revealed that PFKFB3 interacted with GLUD1 and decreased glutamate dehydrogenase (GDH) activity and α-ketoglutarate production. PFKFB3, TNFα, IL-6, IFNγ, CXCL9, CXCL10, CXCL11, MMP13, and MMP19 were downregulated in bone marrow-derived macrophages of conditional PFKFB3-knockout mice relative to those of wild-type mice. Partial PFKFB3 knockdown in macrophages ameliorated the clinical signs of arthritis and bone destruction, inhibited proinflammatory factor expression, and promoted GDH activity and α-ketoglutarate production in tumor necrosis factor-transgenic mice. Single-cell sequencing revealed that macrophages were the most abundant cells in the ankles of arthritic mice, and partial PFKFB3 knockdown promoted M2-like polarization and was correlated with TREM2, SPP1, APOE, and C1Q expression.
CONCLUSION: PFKFB3 is upregulated in macrophages in patients with RA. PFKFB3 aggravates arthritis by modulating macrophage activity, which may be related to decreased α-ketoglutarate production.

Keywords:  Arthritis; Inflammation; Macrophages; PFKFB3; α-Ketoglutarate

DOI:  https://doi.org/10.1016/j.intimp.2025.114102
J Clin Invest. 2025 Jan 30. pii: e187024. [Epub ahead of print]

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxin Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang.

  Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME. Analysis of 18F-FDG uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of Endosulfine alpha (ENSA-K63la), a crucial step that triggers STAT3-CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. Therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Keywords:  Cancer; Cancer immunotherapy; Immunology; Macrophages; Oncology

DOI:  https://doi.org/10.1172/JCI187024
Life Metab. 2023 Oct;2(5): load030

A review collection on immunometabolism.

Ping-Chih Ho, Chenqi Xu, Tiffany Horng.

DOI: https://doi.org/10.1093/lifemeta/load030
bioRxiv. 2025 Jan 20. pii: 2025.01.13.632815. [Epub ahead of print]

Label-free Detection and Characterization of Metabolism in Fresh and Cryopreserved Macrophages.

Daniela De Hoyos Canales, Linghao Hu, Alex J Walsh.

Cryopreservation is a widely used technique to preserve biological samples for extended periods of time at low temperatures. Even though it is known to have significant effects on cell viability, its effect on their metabolism remains unexplored. Studying how cryopreservation influences the metabolism of cells is important to guarantee the reliability of samples transported between sites for analysis. Optical metabolic imaging allows for the study of cellular metabolism in a label-free manner by using the autofluorescence properties of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), two metabolic coenzymes. The goal of this research is to study the metabolic changes in macrophages after cryopreservation and compare these results with freshly isolated macrophage samples to evaluate if the metabolic data is retained after cryopreservation. The metabolism of macrophages was analyzed with fluorescence lifetime imaging microscopy (FLIM) using a multiphoton microscope. Monocytes were isolated from human whole blood and separated into two groups. In Group 1, freshly isolated monocytes were differentiated into macrophages using macrophage-colony stimulating factor (M-CSF) over 8 days. In Group 2, isolated monocytes were cryopreserved after separation from whole blood and then thawed and stimulated with M-CSF for 8 days. Single-cell analysis showed there are significant changes in FLIM parameters between the groups suggesting that the metabolic data of macrophages is altered after a cryopreservation and cell thawing cycle. Our research bridges the current gap by studying the metabolic changes of cells after cryopreservation using a non-invasive and label-free imaging technique.

DOI: https://doi.org/10.1101/2025.01.13.632815
Front Immunol. 2024 ;15 1519639

Cholesterol metabolism regulator SREBP2 inhibits HBV replication via suppression of HBx nuclear translocation.

Fan Yang, Feng Hu, Hongxiao Song, Tie Li, Fengchao Xu, Jing Xu, Le Wang, Fei Wang, Yujia Zhu, Mian Huang, Yanli Gao, Min Rao, Haichun Ma, Guangyun Tan.

  The intricate link between cholesterol metabolism and host immune responses is well recognized, but the specific mechanisms by which cholesterol biosynthesis influences hepatitis B virus (HBV) replication remain unclear. In this study, we show that SREBP2, a key regulator of cholesterol metabolism, inhibits HBV replication by interacting directly with the HBx protein, thereby preventing its nuclear translocation. We also found that inhibiting the ER-to-Golgi transport of the SCAP-SREBP2 complex or blocking SREBP2 maturation significantly enhances HBV suppression. Notably, we demonstrate that the C-terminal domain (CTD) of SREBP2, rather than its N-terminal domain (NTD), mediates this inhibition by interacting with HBx and promoting its extracellular secretion, thus reducing nuclear HBx accumulation. These findings reveal a novel regulatory pathway that links cholesterol metabolism to HBV replication via SREBP2-mediated control of HBx localization. This insight provides a potential basis for new therapeutic strategies against HBV infection, addressing an important global health issue.

Keywords:  HBV - hepatitis B virus; HBV replication; HBx; SREBP2; cholesterol metabolism

DOI:  https://doi.org/10.3389/fimmu.2024.1519639
J Biol Chem. 2025 Jan 23. pii: S0021-9258(25)00069-9. [Epub ahead of print] 108222

Dengue virus is particularly sensitive to interference with long-chain fatty acid elongation and desaturation.

Julia Hehner, Lisa Ludenia, Laura Bierau, Anja Schöbel, Martin Schauflinger, Yvonne F Grande, Dominik Schwudke, Eva Herker.

  Orthoflaviviruses are emerging arthropod-borne pathogens whose replication cycle is tightly linked to host lipid metabolism. Previous lipidomic studies demonstrated that infection with the closely related hepatitis C virus (HCV) changes the fatty acid (FA) profile of several lipid classes. Lipids in HCV-infected cells had more very long-chain and desaturated FAs and viral replication relied on functional FA elongation and desaturation. Here, we systematically analyzed the role of FA elongases and desaturases in infection models of the most prevalent pathogenic orthoflaviviruses, dengue (DENV), Zika (ZIKV), West Nile (WNV), yellow fever (YFV), and tick-borne encephalitis virus (TBEV). Knockdown of desaturases and elongases in Huh7 cells only marginally affected ZIKV, WNV, YFV, and TBEV replication, while DENV titers were strongly reduced. This was most prominent for enzymes involved in very long-chain fatty acid synthesis. In detail, knockdown of the FA elongase ELOVL4, which catalyzes ultra long-chain FA synthesis, significantly reduced DENV titers, decreased the formation of replication intermediates, and lowered viral protein levels in DENV infected hepatoma cells, suggesting a function of ELOVL4 in DENV RNA replication. In contrast, the activity of FA desaturase FADS2, rate-limiting in poly-unsaturated FA biosynthesis, is not involved in viral RNA replication or translation, but is essentially required for formation of infectious DENV particles. Further, in immunocompetent immortalized microglial cells, FADS2 deletion additionally limits viral replication through increased expression of interferon-stimulated genes in response DENV infection. Taken together, enzymes involved in very long-chain FA synthesis are critical for different steps of DENV replication.

Keywords:  fatty acid metabolism; flavivirus; host-pathogen interaction; lipid; polyunsaturated fatty acid (PUFA); virus

DOI:  https://doi.org/10.1016/j.jbc.2025.108222
mBio. 2025 Jan 31. e0302024

Gut microbe-derived betulinic acid alleviates sepsis-induced acute liver injury by inhibiting macrophage NLRP3 inflammasome in mice.

Xuheng Tang, Tairan Zeng, Wenyan Deng, Wanning Zhao, Yanan Liu, Qiaobing Huang, Yiyu Deng, Weidang Xie, Wei Huang.

  Sepsis-induced acute liver injury (SALI) is a prevalent and life-threatening complication associated with sepsis. The gut microbiota plays a crucial role in the maintenance of health and the development of diseases. The impact of physical exercise on gut microbiota modulation has been well-documented. However, the potential impact of gut microbiome on exercise training-induced protection against SALI remains uncertain. Here, we discovered exercise training ameliorated SALI and systemic inflammation in septic mice. Notably, gut microbiota pre-depletion abolished the protective effects of exercise training in SALI mice. Fecal microbiota transplantation treatment revealed that exercise training-associated gut microbiota contributed to the beneficial effect of exercise training on SALI. Exercise training modulated the metabolism of Ligilactobacillus and enriched betulinic acid (BA) levels in mice. Functionally, BA treatment conferred protection against SALI by inhibiting the hepatic inflammatory response in mice. BA bound and inactivated hnRNPA2B1, thus suppressing NLRP3 inflammasome activation in macrophages. Collectively, this study reveals gut microbiota is involved in the protective effects of exercise training against SALI, and gut microbiota-derived BA inhibits the hepatic inflammatory response via the hnRNPA2B1-NLRP3 axis, providing a potential therapeutic strategy for SALI.
IMPORTANCE: Sepsis is characterized by a dysregulated immune response to an infection that leads to multiple organ dysfunction. The occurrence of acute liver injury is frequently observed during the initial stage of sepsis and is directly linked to mortality in the intensive care unit. The preventive effect of physical exercise on SALI is well recognized, yet the underlying mechanism remains poorly elucidated. Exercise training alters the gut microbiome in mice, increasing the abundance of Ligilactobacillus and promoting the generation of BA. Additionally, BA supplementation can suppress the NLRP3 inflammasome activation in macrophages by directly binding to hnRNPA2B1, thereby mitigating SALI. These results highlight the beneficial role of gut microbiota-derived BA in inhibiting the hepatic inflammatory response, which represents a crucial stride toward implementing microbiome-based therapeutic strategies for the clinical management of sepsis.

Keywords:  acute liver injury; betulinic acid; exercise training; gut microbiota; sepsis

DOI:  https://doi.org/10.1128/mbio.03020-24
Hepatol Commun. 2025 Feb 01. pii: e0625. [Epub ahead of print]9(2):

HBV and HBsAg strongly reshape the phenotype, function, and metabolism of DCs according to patients' clinical stage.

Lucile Dumolard, Theophile Gerster, Florent Chuffart, Thomas Decaens, Marie-Noelle Hilleret, Sylvie Larrat, Philippe Saas, Evelyne Jouvin-Marche, David Durantel, Patrice N Marche, Zuzana Macek Jilkova, Caroline Aspord.

BACKGROUND: Hepatitis B is a liver infection caused by HBV. Infected individuals who fail to control the viral infection develop chronic hepatitis B and are at risk of developing life-threatening liver diseases, such as cirrhosis or liver cancer. Dendritic cells (DCs) play important roles in the immune response against HBV but are functionally impaired in patients with chronic hepatitis B. The underlying mechanisms involved in HBV-induced DC dysfunctions remain to be elucidated.
METHODS: We explored DC modulations by HBV and HBsAg by exposing blood-derived cDC1s, cDC2s, and plasmacytoid DCs from healthy donors to HBV or HBsAg and stimulating them with toll-like receptor ligand. Their phenotypic and functional features, as well as their metabolic profile, were analyzed through multiparametric flow cytometry and multiplex assays and further explored on patients' samples.
RESULTS: We found that HBV deeply reshaped the DC secretome in response to toll-like receptor ligand. Strikingly, we observed that HBV-exposed DCs secrete high levels of CX3CL1 (fractalkine), a chemokine responsible for attracting antiviral effectors to the site of infection. HBsAg exposure favored DC activation while drastically altering TRAIL expression in response to toll-like receptor ligand and increasing the secretion of cytokines/chemokines involved in immune tolerance. HBsAg further dampened the metabolism of DC subsets while driving metabolic switches. Notably, the relevance of the CX3CL1/CX3CR1 axis, TGF-β, and metabolic disturbances was demonstrated within intrahepatic DC subsets in patients according to disease stage.
CONCLUSIONS: Our work brings new insights into the immunomodulation induced by HBV on DCs, which contribute to impaired antiviral responses and progression toward chronicity.

DOI: https://doi.org/10.1097/HC9.0000000000000625
iScience. 2025 Jan 17. 28(1): 111692

Hyperglycemic milieu impairs Vγ9Vδ2 T cell functions in tuberculosis patients and prolongs M.tb negative conversion time.

Meiyan Li, Jing Liu, Yanyun Jing, Yanqin Song, Xuezhi Wang, Qinglin Hu, Minjing Hong, Yijia Li, Chan Xiong, Yi Cai, Yangzhe Wu, Yi Hu.

  γδ T cells play protective roles in tuberculosis (TB). Our work demonstrated the therapeutic potential of allogeneic Vγ9Vδ2 T cells in TB patients. However, their functions in TB require further comprehensive evaluation. Here, we compared γδ T cells in TB patients and healthy adults at the bulk and single-cell RNA and protein levels, revealing that impaired glucose metabolism critically undermines their anti-infective functions. Excessive glucose disrupts γδ T cell effector functions, correlating with prolonged sputum smear conversion time in TB patients with type II diabetes. Additionally, serum glucose levels were linked to multidrug-resistant TB. These findings suggest that weakened Vδ2+γδ T cell responses in diabetic TB patients contribute to multidrug resistance. Restoring Vδ2+γδ T cell function offers a promising strategy for TB treatment.

Keywords:  Immunology; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2024.111692
J Inflamm Res. 2025 ;18 1091-1106

Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.

Zhuo-Yu Zhang, Fang Wang, Gang Zhou.

   Purpose: Oral lichen planus (OLP) is a chronic, immune-mediated inflammatory disease involving T cells. Mitochondrial fission plays a crucial role in T cell fate through structural remodeling. Nicotinamide adenine dinucleotide (NAD+) regulates mitochondrial remodeling and function. This study explored the role of NAD+ in modulating mitochondrial fission and apoptosis in T cells under the OLP immune-inflammatory environment.
Patients and Methods: T cells and plasma were isolated from peripheral blood. Mitochondrial morphology was characterized by transmission electron microscopy and Mito-Tracker staining. OLP plasma-exposed Jurkat T cells were infected with the Drp1 shRNA virus to investigate the role of mitochondrial fission in OLP T cell apoptosis. OLP T cells and OLP plasma-exposed Jurkat T cells were treated with either β-nicotinamide mononucleotide (an NAD+ synthesis precursor) or FK866 (an NAD+ synthesis inhibitor) to assess the effect of NAD+ regulation on mitochondrial remodeling and T cell apoptosis.
Results: OLP T cells exhibited fragmented mitochondria with elevated dynamin-related protein 1 (Drp1) and reduced mitofusin 2 (Mfn2) expression, accompanied by decreased apoptosis. Drp1 knockdown in OLP plasma-exposed Jurkat T cells increased apoptosis and reduced proliferation. NAD+ levels were reduced in both OLP T cells and OLP plasma-treated Jurkat T cells, leading to enhanced mitochondrial fission, decreased mitochondrial membrane potential (MMP) and respiration function, and reduced apoptosis rate. β-nicotinamide mononucleotide supplementation restored NAD+ levels, suppressed mitochondrial fission, improved MMP, and promoted apoptosis in these cells.
Conclusion: Reduced NAD+ levels in OLP T cells enhanced mitochondrial fission and contributed to decreased apoptosis. NAD+ supplementation mitigated these effects, suggesting a potential therapeutic strategy for restoring T cell homeostasis in OLP.

Keywords:  T cells; mitochondria; nicotinamide adenine dinucleotide; oral lichen planus

DOI:  https://doi.org/10.2147/JIR.S502273
Nat Commun. 2025 Jan 24. 16(1): 985

Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel.

Yanhong Xing, Meng-Meng Wang, Feifei Zhang, Tianli Xin, Xinyan Wang, Rong Chen, Zhongheng Sui, Yawei Dong, Dongxue Xu, Xingyu Qian, Qixia Lu, Qingqing Li, Weijie Cai, Meiqin Hu, Yuqing Wang, Jun-Li Cao, Derong Cui, Jiansong Qi, Wuyang Wang.

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+-prolyl hydroxylase domain enzymes (PHDs)-NF-κB-interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease.

DOI: https://doi.org/10.1038/s41467-025-56403-x
Lupus Sci Med. 2025 Jan 25. pii: e001401. [Epub ahead of print]12(1):

Metabolic profiles of cutaneous lupus have abnormalities in the nicotinamide adenine dinucleotide pathway.

Laila F Abbas, Grant Barber, Grace Lu, Bahir Chamseddin, Hieu Vu, Ling Cai, Divya Srivastava, Rajiv L Nijhawan, Richard C Wang, Benjamin F Chong.

   OBJECTIVE: Metabolic reprogramming plays a critical role in modulating the innate and adaptive immune response, but its role in cutaneous autoimmune diseases, such as cutaneous lupus erythematosus (CLE), is less well studied. An improved understanding of the metabolic pathways dysregulated in CLE may lead to novel treatment options, biomarkers and insights into disease pathogenesis. The objective was to compare metabolomic profiles in the skin and sera of CLE and control patients using liquid chromatography-mass spectrometry (LC-MS).
METHODS: This was a cross-sectional pilot study comparing metabolomic sera and skin profiles of patients with CLE and normal controls. Patients were recruited from outpatient dermatology clinics at the University of Texas Southwestern and Parkland Health in Dallas, Texas, from January 2019 to October 2020. Skin and serum samples underwent LC-MS analysis. Disease sample metabolite levels were compared with controls, with significance levels adjusted for multiple hypothesis testing.
RESULTS: 17 serum samples (9 CLE, 8 control) and 11 skin samples (5 CLE, 6 control) were analysed using LC-MS, yielding 313 known unique metabolic structures from CLE samples. Patients with CLE were found to have 11 metabolites of differential abundance in the skin, but only 2 in the sera. CLE skin showed increased levels of citrulline (log2 fold change (FC)=1.15, p=0.02) and uracil (log2FC=1.79, p=0.04), and downregulation of cyclic ADP ribose (cADPr) (log2FC=0.83, p=0.04), nicotinamide mononucleotide (NMN) (log2FC=0.75, p=0.016) and nicotinamide adenine dinucleotide (NAD+) (log2FC=0.86, p=0.016) versus control skin. CLE sera had increased arabinose (log2FC=1.17, p=0.02) and cystine (log2FC=1.04, p=0.03) compared with control sera.
CONCLUSIONS: Metabolites associated with the NAD+ pathway may be dysregulated in the skin of patients with CLE. Available treatments including nicotinamide supplementation and anti-CD38 biologics that can correct these abnormalities can be further investigated in patients with CLE.

Keywords:  Autoimmune Diseases; Lupus Erythematosus, Systemic; Therapeutics

DOI:  https://doi.org/10.1136/lupus-2024-001401
Int Immunopharmacol. 2025 Jan 26. pii: S1567-5769(25)00088-8. [Epub ahead of print]148 114099

The absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy-induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation.

Fang Wang, Yanqiao Liu, Yanqin Zhao, Hongyin Zheng, Lei Zhang.

  The immune-responsive gene 1 (IRG1) protein plays a role in various pathological processes by connecting cellular metabolism to a range of cellular activities through the production of itaconate. Recent studies have highlighted the significance of IRG1 and itaconate in bone metabolism and homeostasis. However, the precise role of IRG1 in osteoporosis remains inadequately documented. This study aimed to determine the role of IRG1 in osteoporosis through the utilization of IRG1 knockout (KO) mice and a model of ovariectomy (OVX)-induced osteoporosis. The expression of IRG1 was found to be higher in the bone tissues of postmenopausal osteoporotic mice induced by OVX in comparison to sham control mice. When compared to wild type (WT) mice, OVX-induced bone loss was significantly worse in IRG1 KO mice, and this was accompanied by an increase in osteoclastogenesis and bone resorption. However, the loss of bone and the process of osteoclastogenesis and bone resorption were effectively reversed when the IRG1 KO mice were replenished with itaconate. The osteoclastogenesis induced by receptor activator of nuclear factor kappa-Β ligand (RANKL) in bone marrow-derived macrophages (BMMs) was found to be enhanced by IRG1 deficiency, which could be reversed through the replenishment of itaconate. Further investigation revealed that IRG1 deficiency potentiated the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The inhibition of NLRP3 inflammasome using a targeted inhibitor significantly ameliorated RANKL-induced osteoclastogenesis in IRG1 KO BMMs. Overall, this study highlights the significance of IRG1 in regulating osteoclastogenesis and proposes it as a potential target for osteoporosis treatment.

Keywords:  Immune-responsive gene 1; Inflammasome; Itaconate; Osteoclast; Osteoporosis

DOI:  https://doi.org/10.1016/j.intimp.2025.114099
Front Immunol. 2024 ;15 1537909

Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets.

Huahua Li, Lingling Zou, Zhaowei Long, Junkun Zhan.

   Background: Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined.
Methods: Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets.
Results: In patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways.
Conclusion: This study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.

Keywords:  T cells; immunometabolism; machine learning models; single-cell RNA sequencing; type 2 diabetes mellitus (T2DM)

DOI:  https://doi.org/10.3389/fimmu.2024.1537909