bims-imicid 2025-12-14 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–12–14
38 papers selected by
Dylan Gerard Ryan, Trinity College Dublin

Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
Metabolic reprogramming of macrophages in chronic obstructive pulmonary disease.
Sequestration of the phagocyte metabolite itaconate by Pseudomonas aeruginosa RpoN promotes successful pulmonary infection.
FBP1/HIF-1α Axis mediates macrophage metabolic reprogramming and serves as diagnostic biomarkers in atherosclerosis.
T cell immunometabolic dysfunction in a mouse model of cecal ligation and puncture-induced sepsis.
Sex-Specific Metabolic Programming in Human Neutrophil Subsets.
Macrophages in osteoporotic fractures: from immunometabolic mechanisms to precision therapeutic approaches.
Short-chain fatty acids butyrate and acetate limit Zika virus replication and associated ocular manifestations via the G-protein coupled receptor 43/FFAR2.
Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.
Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.
Temporal metabolic reprogramming in DSS-induced colitis identifies purine metabolism and trigonelline as novel therapeutic targets.
Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism.
Intracellular C. neoformans infection stimulates increased glycolytic activity in fetal liver-derived alveolar-like macrophages.
Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.
Bile acid receptor Tgr5 prevents macrophage hyperinflammation during bacterial sepsis through metabolic and epigenetic silencing.
The role of gut microbiota-derived metabolites in modulating poultry immunometabolism.
Mitochondrial-Targeting Drug-Loaded Nanoparticles Reprogram Macrophage Metabolism via ROS/NO Co-elimination for Diabetic Wound Healing.
Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation.
Interplay between lipid metabolism and macrophage dynamics in ischemic stroke: From mechanistic insights to therapeutic strategies.
Metabolic profiles of the human blood-brain barrier cells treated by TNF-alpha and oxysterols.
Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.
Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn's disease.
Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM-1 Upregulation.
Silencing of S100A11 attenuates murine metabolic dysfunction-associated steatohepatitis.
Uncovering metabolic shifts: an ¹H-NMR study on the dual influence of HIV/TB coinfection and ART.
Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
Dynamic changes in mitochondria support phenotypic flexibility of microglia.
SLC25A1-Mediated Cholesterol Accumulation Promotes Endometriosis Progression by Enhancing Endometrial Stromal Cell Proliferation, Invasion, and M2 Macrophage Polarization.
Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma.
Radiation-induced eCIRP causes macrophage phagocytic dysfunction via mitochondrial impairment and ferroptosis.
DAMP-driven trained immunity: metabolic and epigenetic reprogramming in critical illness and chronic inflammation.
Multiomics analysis of neutrophils in SLE: insights from adult and pediatric disease.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
Glomerular endothelial cells eliminate nicotinamide adenine dinucleotide to instruct CD103+ T cells in human lupus nephritis.
Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.
Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade.
Carnosine as a protective metabolic mediator in inflammatory lung injury by inhibiting macrophage infiltration and M1-like polarization.

Nat Metab. 2025 Dec 09.

Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.

Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Benjamin K Johnson, McLane J Watson, Shixin Ma, Samuel E J Preston, Ryan D Sheldon, Michael P Vincent, Abigail E Ellis, Molly T Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Evan C Lien, Connie M Krawczyk, Russell G Jones.

Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity.

DOI: https://doi.org/10.1038/s42255-025-01415-6
Front Immunol. 2025 ;16 1684075

Metabolic reprogramming of macrophages in chronic obstructive pulmonary disease.

Ziwen Qin, Wenjuan Liu, Chuanjun Huang, Wei Zhang.

  Chronic obstructive pulmonary disease (COPD) is currently one of the major causes of death and hospitalization globally. Pulmonary inflammation and oxidative stress are considered important mechanisms underlying the disease. Recent studies have indicated that the metabolic processes of immune cells in COPD, notably alveolar macrophages (AMs), may undergo significant alterations, exhibiting distinct metabolic characteristics related to their functional state and polarization phenotype. This phenomenon is known as the immunometabolic reprogramming of macrophages. In this article, we review the polarization phenotype and metabolic characteristics of macrophages in COPD, as well as the mechanisms affecting macrophage metabolism, and discuss the potential significance of pathways targeting immunometabolism of AMs in the treatment of COPD.

Keywords:  alveolar macrophages; chronic obstructive pulmonary disease; immunometabolic reprogramming; immunometabolism; macrophage polarization

DOI:  https://doi.org/10.3389/fimmu.2025.1684075
Nat Commun. 2025 Dec 13.

Sequestration of the phagocyte metabolite itaconate by Pseudomonas aeruginosa RpoN promotes successful pulmonary infection.

Ayesha Z Beg, Zihua Liu, Ying-Tsun Chen, Absar Talat, Griffin Gowdy, Jake Miller, Lindsey Florek, Lars Dietrich, Chu Wang, Ian Lewis, Tania Wong Fok Lung, Sebastian Riquelme, Alice Prince.

Inhaled opportunistic pathogens such as Pseudomonas aeruginosa actively modify gene expression to meet the challenges of a new environment. In the infected airway the bacteria must respond to the immunometabolite itaconate, which is abundantly produced by macrophages and has anti-inflammatory and anti-oxidant functions that protect the host from airway damage and causes toxicity to bacteria. As a dicarboxylate that targets cysteine residues, itaconate can modify both bacterial and host proteins often altering metabolic activity. We demonstrate that itaconate promotes a global metabolic response in P. aeruginosa by enhancing the activity of the major alternative transcription factor RpoN. Itaconate is actively transported into the bacteria, induces σ54 rpoN expression and covalently binds cysteine residues 218 and 275 on RpoN helping to neutralize its toxicity. The S-itaconated RpoN exhibits a gain of function driving increased glucose catabolism and enhanced utilization of the bioenergetically efficient Entner-Doudoroff pathway. Thus, the accumulation of itaconate in the infected airway promotes the adaptation of P. aeruginosa to the lung by optimizing its metabolic activity and ability to cause pneumonia.

DOI: https://doi.org/10.1038/s41467-025-67153-1
Int Immunopharmacol. 2025 Dec 11. pii: S1567-5769(25)02001-6. [Epub ahead of print]169 116012

FBP1/HIF-1α Axis mediates macrophage metabolic reprogramming and serves as diagnostic biomarkers in atherosclerosis.

Min Li, Xinxin Liu, XiaoChen Yu, Ao Yin, Xingyu Fu, Xiuru Guan.

  Atherosclerosis (AS)，a major global cause of cardiovascular mortality，is characterized by significant metabolic reprogramming of plaque macrophages in response to a hostile microenvironment containing cytokines, oxidized lipids, and hypoxia. Macrophage metabolic reprogramming, marked by shifts in glycolysis, fatty acid, and amino acid metabolism has emerged as a critical contributor to chronic inflammatory diseases. This study explores the role of fructose-1,6-bisphosphatase 1 (FBP1) in this process and its functional interplay with hypoxia-inducible factor-1α (HIF-1α). Clinically, FBP1 and HIF-1α levels were significantly elevated in peripheral blood mononuclear cells (PBMCs) and serum from AS patients. ROC analysis indicated their strong potential as diagnostic biomarkers. These findings were corroborated in high-fat diet-fed mice and ox-LDL-stimulated macrophages, which showed increased FBP1 and HIF-1α expression in atherosclerotic lesions and immune cells. FBP1 overexpression mitigated ox-LDL-induced metabolic reprogramming, evidenced by reduced lactate production, reactive oxygen species (ROS) generation, and lipid droplet accumulation. Conversely, FBP1 suppression exacerbated these metabolic alterations. Mechanistically, FBP1 directly interacted with and inhibited the expression of HIF-1α. Inhibition of HIF-1α reverses the exacerbation of cellular metabolic reprogramming induced by FBP1 inhibition. In summary, the results demonstrate FBP1/ HIF-1α axis as mediator of macrophage metabolic reprogramming in AS, highlighting its dual significance as a contributor to disease pathogenesis and a promising basis for clinical diagnosis.

Keywords:  Atherosclerosis; Fructose-1, 6-bisphosphatase 1; Hypoxia inducible factor-1α; Macrophage metabolic reprogramming

DOI:  https://doi.org/10.1016/j.intimp.2025.116012
BMC Immunol. 2025 Dec 09.

T cell immunometabolic dysfunction in a mouse model of cecal ligation and puncture-induced sepsis.

Xiaoju Liu, Mai Liting, Peiyu Li, Zhong Chen, Zhijian Yu.

   BACKGROUND: T lymphocyte dysfunction is closely associated with immunosuppression in sepsis, whereas the underlying mechanisms are not fully understood.
RESULTS: In this study, we established a mouse model of cecal ligation and puncture (CLP)-induced sepsis and observed immunometabolic alterations in splenic T cells. Serum energy metabolites related to glycolysis and the tricarboxylic acid (TCA) cycle were imbalanced. Splenic T cells from septic mice showed a shift in subset distribution, with decreased naïve T cells and increased effector populations, along with concurrent activation and exhaustion phenotypes. Notably, mitochondrial mass and mitochondrial membrane potential were significantly diminished in both CD4+ and CD8+ T cell, correlated with increased programmed cell death protein 1 (PD-1) expression. Transmission electron microscopy further confirmed mitochondrial morphological alterations in CLP-derived CD3+ T cells. Furthermore, seahorse assays demonstrated impaired metabolic reprogramming capacity in activated CLP splenic CD3+ T cells, with suppressed glycolytic and oxidative phosphorylation responses. This impairment was coupled with reduced fold-increases in mitochondrial mass and mitochondrial membrane potential levels upon activation in both CD4+ and CD8+ T cell compared to controls. Clinically, peripheral T cells from septic patients showed elevated CD69 and PD-1 expression, a significant increase in CD39 and a decrease in CD73, increased mitochondrial mass and decreased mitochondrial membrane potential, particularly in those with septic shock.
CONCLUSIONS: Our findings provide several layers of T cell dysfunction in sepsis, linking subset redistribution, an exhausted phenotype, mitochondrial impairment, and reduced proliferative capacity, suggesting that future therapeutic interventions aiming to reverse sepsis-induced immunosuppression may require a combinatorial approach.

Keywords:  Immune metabolism; Mitochondrial mass; Mitochondrial membrane potential; Sepsis; T cell

DOI:  https://doi.org/10.1186/s12865-025-00790-9
J Leukoc Biol. 2025 Dec 12. pii: qiaf179. [Epub ahead of print]

Sex-Specific Metabolic Programming in Human Neutrophil Subsets.

Anjali S Yennemadi, Faye K Murphy, Joseph Keane, Gina Leisching.

  While sex differences in neutrophil metabolism have been documented, whether this metabolic dimorphism extends to specific neutrophil subsets remains unknown.LDNs are characterized by their lower buoyant density compared to normal-density neutrophils(NDNs), are present in low numbers in healthy individuals, and are often associated with disease severity and immune dysregulation.LDNs and normal-density neutrophils (NDNs) from healthy human donors were isolated whereafter cellular metabolism specifically oxidative phosphorylation and glycolysis, alongside flow cytometry for maturity markers (CD16hi/lo) was assessed.Male LDNs exhibited significantly higher basal OCR and ATP production than female LDNs, while no sex differences were observed in NDNs. Strikingly, male LDNs also had higher OCR and glycolysis than their matched NDNs, whereas female LDNs were exhibited a lower OCR than their NDNs.Our study reveals subset-specific sexual metabolic reprogramming in LDNs whereby male LDNs exhibit a hypermetabolic phenotype. These findings provide a metabolic basis for sex-biased immune responses and highlight the need for sex-stratified approaches in neutrophil-targeted therapies.

Keywords:  Low density neutrophils; metabolism; mitochondria; neutrophils; oxygen consumption rate; sex difference

DOI:  https://doi.org/10.1093/jleuko/qiaf179
Front Endocrinol (Lausanne). 2025 ;16 1698647

Macrophages in osteoporotic fractures: from immunometabolic mechanisms to precision therapeutic approaches.

Jiahui Xing, Haibo Li, Honggang Xia, Lilei Xia, Hongzhou Zhao.

  Osteoporosis (OP) is a systemic bone disease characterized by reduced bone mass and deterioration of bone microarchitecture. Its critical complication, osteoporotic fractures (OPF), imposes a significant global disease burden. Macrophages, serving as central regulators within the osteoimmune microenvironment, dynamically modulate bone homeostasis and fracture healing through polarization (into pro-inflammatory M1 and reparative M2 phenotypes) and metabolic reprogramming. In OPF, OP-inducing factors (such as estrogen deficiency and aging) induce metabolic dysregulation in macrophages by disrupting the balance between glycolysis and oxidative phosphorylation (OXPHOS), causing aberrant succinate accumulation, and depleting NAD+ levels. This dysregulation disrupts the orderly transition from pro-inflammatory M1 to reparative M2 polarization, ultimately leading to insufficient inflammatory initiation in the early fracture phase and impaired osteogenic differentiation during later stages. Targeting this mechanism, innovative therapeutic strategies centered on macrophage metabolic reprogramming and polarization modulation are rapidly developing. These include nanocarriers for mitochondrial function restoration, bioactive coatings enabling time-programmed osseointegration, immunomodulatory smart hydrogels, and functionalized composite biomaterials. These strategies effectively promote osteoporotic bone regeneration by synergistically optimizing osteoimmune homeostasis and the osteoblast-osteoclast balance. This review systematically summarizes the immunometabolic mechanisms of macrophages in OPF and explores targeted intervention strategies, providing novel perspectives for the precision treatment of OPF.

Keywords:  immunometabolism; macrophages; metabolic reprogramming; osteoporotic fractures; polarization; targeted therapy

DOI:  https://doi.org/10.3389/fendo.2025.1698647
J Virol. 2025 Dec 08. e0182625

Short-chain fatty acids butyrate and acetate limit Zika virus replication and associated ocular manifestations via the G-protein coupled receptor 43/FFAR2.

Nikhil Deshmukh, Prince Kumar, Lal Krishan Kumar, Vaishnavi Balendiran, Pawan Kumar Singh.

  Short-chain fatty acids (SCFAs) are gut microbial metabolites produced by gut microbiota from dietary fiber. SCFAs have shown both pro- and anti-viral roles among different viruses and are known to regulate immune functions during infections. However, their role against the Zika virus (ZIKV), in general, and ocular infection, in particular, has never been investigated. In the present study, we aimed to examine the role of three SCFA derivatives: phenylbutyrate (PBA), sodium butyrate (NaB), and sodium acetate (NaAC), on ZIKV replication and associated ocular complications using primary human trabecular meshwork cells (HTMCs) and an IFNAR1-deficient mouse model of ocular infection. Our findings reveal that PBA and NaAc treatment dramatically suppressed the ZIKV replication in HTMCs. NaB showed a slightly less effect than PBA and NaAc. PBA and NaAc treatment significantly attenuated the ZIKV-induced inflammatory cytokine, interferons, and interferon-stimulated genes response via antagonizing the RIG-I/NFκB/MAPKs/STAT1-3 signaling pathways. We discovered that ZIKV induces the expression of free fatty acid receptor 2 (FFAR2)/GPR43 in HTMCs, which is further potentiated by PBA/NaAc. Pharmacological inhibition of FFAR2 abrogated the protective abilities of PBA/NaAc and significantly increased viral replication. Blocking FFAR2 receptors promoted ZIKV-induced cell death, which was suppressed by PBA and NaAc. Butyrate and acetate also inhibited ZIKV binding and cellular entry and inactivated the virus before internalization. PBA and NaAc treatment in mice attenuated the ZIKV-induced ocular manifestations (intraocular pressure, RPE/retinal atrophy, and TM/anterior segment inflammation), which was abrogated by FFAR2 inhibition by 4-CMTB, a selective pharmacological inhibitor of FFAR2. Collectively, our findings indicate that SCFA treatment is an effective approach to limit ZIKV replication and associated ocular damage and may be worth exploring as a means to treat or prevent ZIKV-induced ocular complications/glaucoma in humans.IMPORTANCEZIKV is known to cause severe ocular manifestations in in-utero exposed infants; however, the molecular mechanisms of ZIKV-induced ocular complications remain unknown. SCFAs have demonstrated both pro- and anti-viral roles against different viruses; however, their role against ZIKV is unknown. We showed that SCFAs butyrate and acetate suppress ZIKV transmission and associated ocular complications. The anti-ZIKV activity of these SFACs is mediated via FFAR2, and pharmacological inhibition of FFAR2 promotes ZIKV-induced inflammatory and cell death responses, as well as ocular malformations.

Keywords:  Zika virus; acetate; butyrate; eye; glaucoma; inflammation; intraocular pressure; retinal atrophy; trabecular meshwork

DOI:  https://doi.org/10.1128/jvi.01826-25
Res Sq. 2025 Dec 04. pii: rs.3.rs-8195970. [Epub ahead of print]

Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.

Melanie McReynolds, Abrar Alsaadi, Lina Welz, Anant Pothakamury, Clara Gilloteau, Praveena Prasad, Mahmoud Yahia, Jaedon Sadler, Jaclyn Smith, Brenita Jenkins, Garret Diven, Johanna Bornhäuser, Taous Mekdoud, Shuchang Tian, Philip Rosenstiel, Stefan Schreiber, Jordan Bisanz, Konrad Aden.

Host-microbiota metabolic interactions critically regulate nicotinamide adenine dinucleotide (NAD+) homeostasis, and their disruption is increasingly linked to chronic diseases including inflammatory bowel disease (IBD). However, it remains unclear whether NAD+ dysregulation in IBD arises from impaired production, enhanced consumption, or both. Using multi-omics approaches and stable isotope-labeled NAD+ precursors administered via intravenous infusion in a murine model of dextran sulfate sodium (DSS)-induced colitis, we mapped tissue- and lumen-specific NAD+ metabolism under inflammatory stress. Our results reveal tissue-specific rewiring of NAD+ metabolism, with increased flux through the salvage pathway compensating for reduced de novo NAD+ synthesis from tryptophan. In parallel, microbial de novo NAD+ production was elevated, highlighting a cooperative host-microbiota response to inflammatory stress. These findings demonstrate differential regulation of NAD+ biosynthesis during acute colitis and underscore the dynamic interplay between host and microbial metabolism in maintaining NAD+ homeostasis under inflammatory conditions.

DOI: https://doi.org/10.21203/rs.3.rs-8195970/v1
J Biochem. 2025 Dec 11. pii: mvaf080. [Epub ahead of print]

Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.

Akimitsu Konishi.

  Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed NHE1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits HDAC activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.

Keywords:  Cellular senescence; Glycolysis; Inflammation; Intracellular acidification; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1093/jb/mvaf080
Front Pharmacol. 2025 ;16 1691978

Temporal metabolic reprogramming in DSS-induced colitis identifies purine metabolism and trigonelline as novel therapeutic targets.

Qi Zhang, Jianguo Wang, Long Zhang, Kangjie Song, Xiaoming Sun, Yaming Zhang, Fubao Liu.

   Background: Inflammatory bowel disease (IBD) is a multifactorial disorder characterized by aberrant immune activation and metabolic dysregulation. Despite significant advances in understanding immune mechanisms, the temporal dynamics of metabolic alterations during intestinal inflammation and their therapeutic implications remain poorly defined.
Methods: To investigate metabolic reprogramming during colitis progression, we conducted time-resolved metabolomic profiling of the colon, mesenteric lymph nodes (MLNs), and serum in a dextran sulfate sodium (DSS)-induced murine colitis model at days 1, 3, 5, and 7 post-induction. Targeted and untargeted metabolomic analyses were integrated with pathological and immunological assessments. To assess therapeutic relevance, DSS-treated mice were administered either trigonelline, a metabolite identified in serum, or mycophenolic acid (MPA), a purine metabolism inhibitor, separately. Metabolomic profiling revealed a progressive activation of purine metabolism in colonic tissues and MLNs, correlating with enhanced immune-inflammatory responses.
Results: Trigonelline was identified as a serum biomarker positively associated with disease severity. Therapeutic treatment with either trigonelline or MPA significantly alleviated histopathological damage, reduced inflammatory cell infiltration in both the colon and MLNs, and restored the Th17/Treg cell balance. Mechanistic studies indicated that trigonelline and MPA individually suppress pro-inflammatory signaling pathways while promoting regulatory immune responses.
Conclusion: This study provides a comprehensive temporal map of metabolic reprogramming during colitis progression and identifies purine metabolism and trigonelline as novel therapeutic targets. These findings highlight the translational potential of multi-organ metabolomic approaches in elucidating disease mechanisms and guiding precision treatment strategies for IBD and related inflammatory conditions.

Keywords:  inflammatory; inflammatory bowel disease; metabolomic; purine metabolism; trigonelline

DOI:  https://doi.org/10.3389/fphar.2025.1691978
JCI Insight. 2025 Dec 08. pii: e192774. [Epub ahead of print]10(23):

Targeting the pentose phosphate pathway mitigates graft-versus-host disease by rewiring alloreactive T cell metabolism.

Saeed Daneshmandi, Eun Ko, Qi Yan, Jee Eun Choi, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa Wm Fan, Jingxin Qiu, Sophia Hani, Keli L Hippen, Jianmin Wang, Philip L McCarthy, Bruce R Blazar, Hemn Mohammadpour.

  Glycolysis fuels cytotoxic allogeneic T cells in acute graft-versus-host disease (aGvHD), but the downstream role of glucose metabolism in modulating aGvHD remains unclear. Targeting glycolysis or glucose receptors is toxic. Therefore, we explored alternative glucose-dependent pathways, focusing on the pentose phosphate pathway (PPP). Single-cell RNA sequencing revealed PPP upregulation in allogeneic T cells during allogeneic hematopoietic cell transplantation (allo-HCT). We showed that donor T cell deficiency in 6-phosphogluconate dehydrogenase (6PGD), the second rate-limiting enzyme in the PPP, significantly reduced aGvHD severity and mortality in murine models. Functional assays demonstrated that PPP blockade led to proliferation arrest without inducing apoptosis. PPP blockade shifted T cell metabolism away from T cell dependency on glycolysis for rapid T cell proliferation. Pharmacological inhibition of the PPP through 6PGD blockade with 6-aminonicotinamide (6AN) effectively reduced aGvHD severity, like donor 6PGD-deficient T cells in an allogeneic aGvHD model. Similarly, 6AN reduced xenogeneic GvHD lethality. 6PGD inhibition preserved the graft-versus-tumor (GvT) effect, with the generation of a small subset of granzyme Bhi effector T cells with potent antitumor activity. These findings highlight the PPP as a key regulator of allogeneic T cell proliferation and differentiation and identify 6PGD as a promising therapeutic target to mitigate aGvHD severity while preserving beneficial GvT effects.

Keywords:  Immunology; Oncology; Stem cell transplantation; T cells

DOI:  https://doi.org/10.1172/jci.insight.192774
bioRxiv. 2025 Dec 02. pii: 2025.11.28.690224. [Epub ahead of print]

Intracellular C. neoformans infection stimulates increased glycolytic activity in fetal liver-derived alveolar-like macrophages.

Derek A Wiggins, Josh B Griggs, Andrew M England, Emily N Callison, Cedra H Kamel, Cathrine A Hasan, Anna E Davis, Morgan E Chappell, Kayla N Conner-Halim, Andrew J Olive, Erin E McClelland, Rachel N Leander, Rebecca L Seipelt-Thiemann, David E Nelson.

Alveolar macrophages (AMs) serve as a first line of defense against respiratory pathogens, including Cryptococcus neoformans , the primary causative agent of cryptococcosis, a deadly pulmonary mycosis which commonly afflicts immunocompromised individuals. While these innate immune cells are thought to play a pivotal role in controlling the outcome of C. neoformans infections, this critical host-pathogen interaction is more commonly studied in vitro using bone marrow-derived macrophages (BMDM) or immortalized macrophage cell lines that differ in ontogeny and phenotype from AMs. In this work, we characterized fetal liver-derived alveolar-like macrophages (FLAMs) as an alternate model to study the earliest stages of C. neoformans infection. Here, we show that the FLAM steady state transcriptome is more similar to primary AMs than peritoneal macrophages and the macrophage cell lines, RAW264.7 and J774, and that FLAMs exhibit distinct transcriptional responses to IFNγ stimulation and C. neoformans infection compared to J774 cells. Specifically, transcriptome profiling and gene ontology analysis indicate that C. neoformans infection of FLAMs, but not J774 cells, increases the expression of canonical glycolytic genes, including Slc2a1, Pgk1, and Ldha , which is accompanied by a metabolic shift favoring glycolysis. Furthermore, activation or inhibition of hypoxia inducible factor 1 (HIF1) activity utilizing dimethyloxalylglycine (DMOG) and echinomycin, respectively, indicates that the expression of select glycolytic genes in C. neoformans -infected FLAMs is HIF1-dependent. Collectively, our results suggest that FLAMs serve as an appropriate tool for modeling AM: C. neoformans interactions and investigating the effects of this pathogen on host AM immunometabolism.

DOI: https://doi.org/10.1101/2025.11.28.690224
Nat Commun. 2025 Dec 11.

Lypd6b depletion promotes CD8+ T cell-mediated anti-tumor immunity via metabolic reprogramming in colorectal cancer.

Ting Liu, Fanxin Zeng, Zuyin Li, Leirong Cheng, Xuanxuan Yan, Haiqiang Chen, Qin Liu, Xue Li, Zhao Li, Jiaheng Yao, Dan Xu, Zhinan Chen, Fengchao Wang, Jun Wang, Jinhua Zhang.

Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly identified molecule associated with neuromodulation. However, the role of Lypd6b in regulating the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b-/-) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation in a PI3K/mTOR/LDHA pathway-dependent manner. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.

DOI: https://doi.org/10.1038/s41467-025-67344-w
iScience. 2025 Dec 19. 28(12): 113929

Bile acid receptor Tgr5 prevents macrophage hyperinflammation during bacterial sepsis through metabolic and epigenetic silencing.

Maria Reich, Tobias Franz, Haifeng C Xu, Paulina Philippski, Jan Stindt, Sandra Freier, Anja Sammt, Kristina Schoonjans, Philipp A Lang, Sascha Kahlfuß, Verena Keitel.

  Tgr5 is a membrane-bound bile acid receptor that negatively regulates immune cells, although the molecular mechanisms behind this observation remain elusive. Here we report that Tgr5 is upregulated in macrophages during stimulation with Listeria monocytogenes and that Tgr5-deficient macrophages are hyperinflammatory and mice with myeloid Tgr5 deficiency are more susceptible to Listeria monocytogenes sepsis. Unexpectedly, Tgr5-deficient macrophages show reduced glycolysis and ATP citrate lyase expression, which cumulates in acetyl-CoA deficiency and impaired metabolic-epigenetic gene silencing, driving macrophages toward a hyperinflammatory phenotype during bacterial sepsis.

Keywords:  biological sciences; immunology; microbiology; natural sciences

DOI:  https://doi.org/10.1016/j.isci.2025.113929
Front Physiol. 2025 ;16 1700406

The role of gut microbiota-derived metabolites in modulating poultry immunometabolism.

O E Oke, L O Fasasi, I O Opowoye, O A Akosile.

  The poultry sector is crucial to global food security, but it faces increasing challenges from heat stress, viral diseases, and restrictions on antibiotic use. These stressors highlight immunometabolism, the junction of immune function and metabolic pathways, as a crucial factor in determining the productivity and health of poultry. There is growing evidence that the gut microbiota is a dynamic metabolic organ that produces a diverse range of bioactive metabolites in addition to its function in nutritional digestion. The immunometabolism of poultry is significantly influenced by these microbiota-derived metabolites, including short-chain fatty acids, bile acid derivatives, amino acid catabolites, vitamins, and polyamines. Disease resistance, vaccination responsiveness, and stress adaptability are shaped by their modulation of intestinal barrier integrity, energy balance, oxidative stress resilience, and immune cell activation. This review summarises what is currently known about the functional diversity and composition of the gut microbiota in poultry, describes the concept of immunometabolism in birds, and assesses the mechanisms by which microbial metabolites regulate metabolic and immunological crosstalk. Prebiotics, probiotics, synbiotics, postbiotics, phytochemicals, and other nutritional and managerial interventions that improve advantageous metabolite profiles are given particular consideration. Applications to enhance poultry health, alleviate heat stress, reduce reliance on antibiotics, and promote sustainable production are also discussed. For mapping metabolite-immune interactions, emerging methods such as germ-free models, metabolomics, metagenomics, and systems biology approaches are emphasised as revolutionary. Metabolites produced by the gut microbiota are crucial to poultry immunometabolism and offer promising opportunities for precision nutrition and healthcare. Bridging the existing research gaps using integrative, multidisciplinary methods to promote sustainable and resilient poultry production is needed. This review centres on the mechanistic axis linking gut microbiota-derived metabolites to host immunometabolic regulation, tracing the pathway from metabolite generation through receptor activation and immune-metabolic reprogramming to measurable phenotypic outcomes in poultry.

Keywords:  gut microbiota; immunometabolism; metabolite; nutrition; poultry

DOI:  https://doi.org/10.3389/fphys.2025.1700406
ACS Appl Mater Interfaces. 2025 Dec 12.

Mitochondrial-Targeting Drug-Loaded Nanoparticles Reprogram Macrophage Metabolism via ROS/NO Co-elimination for Diabetic Wound Healing.

Xuan Zhou, Zhidan Huang, Huake Yang, Linbo Jin, Yiming Zhang.

  Diabetic wounds pose a growing healthcare challenge, characterized by heavy M1 macrophage infiltration, reactive oxygen species (ROS) overproduction, tissue hypoxia, and cytokine storms. The diabetic microenvironment fails to support the critical M1-to-M2 macrophage phenotypic switch, trapping tissues in persistent pathological inflammation that disrupts natural healing processes. In this study, we developed triphenylphosphonium (TPP)-modified mitochondria-targeting nanoparticles, where liposomes encapsulated two metabolomically guided agents: aminooxyacetic acid (AOAA) to suppress nitric oxide (NO) production and hollow mesoporous manganese dioxide (H-MnO2) to scavenge mitochondrial ROS and supply O2. In vitro, after successful mitochondrial internalization by macrophages, the nanoparticles reduced NO and ROS levels, enhanced mitochondrial respiration, and reprogrammed macrophage metabolism─shifting from aerobic glycolysis to oxidative phosphorylation (OXPHOS). This metabolic shift drove macrophage transition from pro-inflammatory M1 to anti-inflammatory M2 and thus resolved aberrant inflammation. In diabetic murine wound models, TPP-L@H-MnO2@AOAA further validated its efficacy. By modulating macrophage repolarization, it promoted re-epithelialization and collagen deposition. Overall, these anti-inflammatory nanoparticles with sustained-release capability provide a promising therapeutic tool for clinical management of diabetic wounds.

Keywords:  anti-inflammatory; diabetic wound healing; macrophages; metabolic reprogramming; mitochondrial targeting

DOI:  https://doi.org/10.1021/acsami.5c19664
Immunity. 2025 Dec 10. pii: S1074-7613(25)00520-5. [Epub ahead of print]

Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation.

Chantal Wientjens, Maria Doverman, Jelena Zurkovic, Tushar More, Jayagopi Surendar, Svetozar Nesic, Carola Sarici, Timon D Utecht, Johanna Pohl, Jonathan Pollock, David Voehringer, Karsten Hiller, Christoph Thiele, Christoph Wilhelm.

  Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.

Keywords:  GPX4; ILC2; ROS; asthma; cysteine; fatty acids; ferroptosis; innate lymphoid cells; lipid metabolism; thioredoxin

DOI:  https://doi.org/10.1016/j.immuni.2025.11.018
Int Immunopharmacol. 2025 Dec 08. pii: S1567-5769(25)01978-2. [Epub ahead of print]169 115990

Interplay between lipid metabolism and macrophage dynamics in ischemic stroke: From mechanistic insights to therapeutic strategies.

Jiagui Huang, Heng Yang, Li Zhong, Yan He, Qin Yang.

  Ischemic stroke (IS), a leading global cause of long-term disability, is treated with therapies (e.g., thrombolysis, mechanical thrombectomy) constrained by a narrow therapeutic window and ischemia-reperfusion injury risks. Neuroinflammation-exhibiting dual, time-dependent (protective vs. harmful) effects-complicates static targeting. Macrophages, encompassing resident microglia and infiltrating blood-derived macrophages, regulate neuroinflammation via marked heterogeneity and metabolic reprogramming in the dynamic IS microenvironment. Herein, we review metabolic reprogramming in the IS milieu, lipid metabolism in IS-associated macrophages, its functional consequences, therapeutic targets, and emerging approaches. Additionally, we address current challenges and future directions, and highlight translational perspectives in IS. In summary, macrophages emerge as metabolic hubs in IS, with lipid metabolism as a critical targetable axis for improving stroke therapy.

Keywords:  Ischemic stroke; Lipid metabolism; Macrophage; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.intimp.2025.115990
Biomed Pharmacother. 2025 Dec 05. pii: S0753-3322(25)01047-9. [Epub ahead of print]193 118853

Metabolic profiles of the human blood-brain barrier cells treated by TNF-alpha and oxysterols.

Cindy Nguyen, Kenneth C P Cheung, Xiaoli Chen, Julien Saint-Pol, Fumitaka Shimizu, Takashi Kanda, Caroline Pot, Maxime Culot, Kannie W Y Chan, Wang Lu, Aiping Lyu, Wei Jia, Fabien Gosselet.

  The blood-brain barrier (BBB) is essential for central nervous system homeostasis, and its dysfunction is implicated in neuroinflammatory disorders such as Alzheimer's disease and multiple sclerosis. Oxysterols, cholesterol-derived metabolites, modulate lipid metabolism, immune responses, and BBB physiology, but their specific metabolic effects remain poorly defined. Using an in vitro human BBB model, we examined the impact of tumor necrosis factor-α (TNFα) and selected oxysterols (24S-hydroxycholesterol, 25-hydroxycholesterol, 7α,25-dihydroxycholesterol) on metabolomic profiles of brain-like endothelial cells (hBLEC) and pericytes (hBP) via targeted LC-MS/MS analysis of over 300 metabolites. TNFα markedly increased phenylpyruvic acid, indicating dysregulated phenylalanine metabolism. Oxysterols elicited minimal effects in hBLEC, but significantly altered glycolysis and fatty acid metabolism in hBP, notably reducing fructose 6-phosphate, glucose 6-phosphate, and myristoleic acid, while increasing specific fatty acids under inflammatory conditions. These results identify phenylpyruvic acid as a candidate biomarker of BBB inflammation and highlight pericyte metabolic reprogramming as a key mechanism of oxysterol action.

Keywords:  Blood-brain barrier; Oxysterols; Pericytes, fatty acids; Phenylpyruvic acid; TNFα

DOI:  https://doi.org/10.1016/j.biopha.2025.118853
Autophagy. 2025 Dec 11.

Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.

Lisa Mayr, Julian Schwärzler, Laura Scheffauer, Zhigang Rao, Dietmar Rieder, Felix Grabherr, Moritz Meyer, Jakob Scheler, Almina Jukic, Luis Zundel, Verena Wieser, Andreas Zollner, Anna Simonini, Stefanie Auer, Lisa Amann, Maureen Philipp, Johannes Leierer, Richard Hilbe, Günter Weiss, Patrizia Moser, Philip Rosenstiel, Qitao Ran, Richard S Blumberg, Arthur Kaser, Andreas Koeberle, Zlatko Trajanoski, Herbert Tilg, Timon E Adolph.

  Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.Abbreviations: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.

Keywords:  ATG16L1; Crohn disease; glutathione peroxidase 4; intestinal epithelial cells; intestinal inflammation; polyunsaturated fatty acids

DOI:  https://doi.org/10.1080/15548627.2025.2600906
Cell Metab. 2025 Dec 08. pii: S1550-4131(25)00492-9. [Epub ahead of print]

Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn's disease.

IBDome Consortium

  Westernization of diet, partly characterized by long-chain fatty acid excess, perturbs intestinal immune responses in Crohn's disease (CD). The cellular and molecular framework of lipid sensing in intestinal inflammation remains enigmatic. By small intestinal transcriptional profiling of CD, we identified increased transcriptional activity of retinoid X receptor alpha (RXRα) specifically in intestinal epithelial cells (IECs). Transcriptional RXRα activity was induced in IECs of mice by ω-3 and ω-6 polyunsaturated fatty acid (PUFA) excess in a Western diet. PUFA-induced RXRα activity in Paneth cells governed chronic transmural enteritis by enabling the expression of CXCL1. Oral exposure to isotretinoin ameliorated PUFA-induced metabolic enteritis in two mouse models, and isotretinoin therapy reduced the odds of developing CD in an analysis of electronic health care records from 170,597 patients. Collectively, we identify RXRα in Paneth cells as a metabolic stress sensor that enables enteritis, providing novel perspectives for the prevention and treatment of CD.

Keywords:  CD; Crohn’s disease; IBD; Paneth cell; RXRa; Western diet; inflammatory bowel diseases; intestinal inflammation; metabolic inflammation; retinoid X receptor alpha

DOI:  https://doi.org/10.1016/j.cmet.2025.11.008
Exp Dermatol. 2025 Dec;34(12): e70186

Metabolic and Vascular Inflammation in Alopecia Areata: Linking Uric Acid, Lipid Imbalance and ICAM-1 Upregulation.

Madoc Dawson, Derek Pye, Rebecca Mahon, George Taylor, Asim Shahmalak, Bessam Farjo, Nilofer Farjo, Matthew Harries, Talveen S Purba.

Alopecia areata (AA) is an inflammatory hair loss disorder caused by an immune-mediated attack of the hair follicle (HF) bulb. Active disease is characterised by a peribulbar proinflammatory infiltrate, HF immune privilege collapse and premature catagen induction, yet the underlying drivers of AA remain poorly understood. With comparable autoimmune inflammatory conditions displaying metabolic alterations, we hypothesised that AA is marked by similar pathobiological changes. To investigate this, we utilised an exploratory metabolomics-based discovery liquid chromatography mass spectrometry (LC-MS) approach. This yielded 32 putatively annotated metabolites significantly altered between lesional and nonlesional AA scalp. Notably, 13-HODE, a linoleic acid metabolite linked to vascular function, was decreased, whilst uric acid (UA), a purine degradation metabolite linked to vascular dysfunction, was increased in the lesional scalp. Moreover, serum LC-MS revealed elevated UA in AA compared to controls, which is linked to systemic endothelial dysfunction. CD31+/ICAM-1+ immunofluorescence co-expression analysis revealed elevated vascular inflammation and endothelial cell activation in the AA scalp. We also experimentally provoked the same response in ex vivo human HF culture via UA or fructose (which increases UA) supplementation. Interestingly, the fructose-generating polyol pathway enzymes, AKR1B1 and SORD, are expressed in the HF, with significantly increased AKR1B1 immunoreactivity in lesional AA HFs, suggesting that fructose can be locally generated by the HF and may contribute to elevated UA levels in AA. Together, these metabolic changes point towards UA-linked microvascular dysfunction in AA, inviting exploration of whether strategies to improve endothelial function and regulate UA are effective in managing AA.

DOI: https://doi.org/10.1111/exd.70186
NPJ Gut Liver. 2025 ;2(1): 32

Silencing of S100A11 attenuates murine metabolic dysfunction-associated steatohepatitis.

P V Daniel, Gyanendra Puri, Yixing Luo, Naresh Golla, Takahito Nishihara, Hanna Erickson, George Marek, Nagaswaroop Kengunte Nagaraj, Davide Povero, Amy S Mauer, Jun Liu, Harmeet Malhi.

  Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by insulin resistance and impaired hepatic metabolism, which lead to steatosis and lipotoxicity. S100A11, an alarmin upregulated in MASH, promotes steatosis in vitro, but its role in vivo remains unclear. We hypothesized that S100A11 drives MASH by upregulating hepatic lipid synthesis. Using whole-body S100a11 knockout (S100a11 -/- ) mice on a MASH-inducing diet, we found S100a11 deficiency reduced steatosis, inflammation, and fibrosis. Hepatotropic AAV8-mediated silencing of S100a11 confirmed these findings. Bulk RNA sequencing with Ingenuity Pathway Analysis revealed dysregulated carbohydrate and lipid metabolism in S100a11 -/- livers, including downregulation of hexokinase 2 (Hk2). Since hexokinases regulate glucose flux into downstream metabolic processes, we overexpressed HK2 in S100a11 -/- mice, which was sufficient to increase steatosis. Further, palmitate-induced HK2 upregulation required S100A11 in a human hepatocyte cell line. These studies identify HK2 as a downstream target of S100A11, both of which are potential therapeutic targets for MASH.

Keywords:  Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis

DOI:  https://doi.org/10.1038/s44355-025-00044-w
BMC Infect Dis. 2025 Dec 12.

Uncovering metabolic shifts: an ¹H-NMR study on the dual influence of HIV/TB coinfection and ART.

Steven Patrick Ahumada Prado, Shayne Mason, Robin Wood, Laneke Luies.

   BACKGROUND: Human immunodeficiency virus (HIV) and tuberculosis (TB) coinfection pose a substantial global health burden, with each infection amplifying the immune and metabolic impacts of the other. Investigating the compounded metabolic disruptions in HIV/TB coinfection and how these are modulated by antiretroviral therapy (ART) offers information into disease mechanisms and therapeutic strategies.
METHODS: This study used untargeted proton nuclear magnetic resonance metabolomics to characterize the urine samples from three participant groups: healthy controls, treatment-naive HIV/TB coinfected individuals, and ART-treated HIV/TB coinfected individuals.
RESULTS: Significant metabolite shifts were observed across gut microbiota, energy, amino acid, and carbohydrate metabolism. Metabolomic profiles of HIV/TB coinfection suggested mitochondrial perturbation, markers of insulin resistance, and microbial dysbiosis. ART was associated with partial restoration of mitochondrial function, stabilization of gut microbiota, and reduced oxidative stress. However, glucose dysregulation appeared to persist. Key metabolites, including phenylacetylglycine and trans-aconitic acid, emerged as potential differential markers for coinfection and treatment response.
CONCLUSION: ART modulates metabolic pathways disrupted by HIV/TB coinfection, showing partial improvements but leaving glucose metabolism dysregulated. These findings highlight the potential of targeted metabolic monitoring to optimize coinfection treatment strategies. Further investigations are needed in larger cohorts to validate these results and better understand coinfection pathophysiology.

Keywords:  Antiretroviral therapy (ART); Gut microbiota; HIV/TB coinfection; Human immunodeficiency virus (HIV); Metabolic biomarkers; Mitochondrial stress; Tuberculosis (TB); ¹H-NMR metabolomics

DOI:  https://doi.org/10.1186/s12879-025-12088-7
Nat Metab. 2025 Dec 08.

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.

Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F Fearnside, Richard H Barton, Ana Luisa Neves, Alice R Rothwell, Christelle Gérard, Sophie Calderari, Mark J Williamson, Julian E Fuchs, Lata Govada, Claire L Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C Glen, Nigel J Gooderham, Jeremy K Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P Liu, Patrice D Cani, Marc-Emmanuel Dumas.

The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA-unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease-improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial-mammalian chemical crosstalk.

DOI: https://doi.org/10.1038/s42255-025-01413-8
Nat Commun. 2025 Dec 12. 16(1): 11103

Dynamic changes in mitochondria support phenotypic flexibility of microglia.

Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.

Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.

DOI: https://doi.org/10.1038/s41467-025-66709-5
Int J Biol Sci. 2026 ;22(1): 466-480

SLC25A1-Mediated Cholesterol Accumulation Promotes Endometriosis Progression by Enhancing Endometrial Stromal Cell Proliferation, Invasion, and M2 Macrophage Polarization.

Pusheng Yang, Tao Wang, Yaxin Miao, Wenwen Liu, Yiping Zhu, Jing Sun.

  Endometriosis is an estrogen-dependent chronic inflammatory disorder. Cholesterol (CHO) has been reported to be closely associated with estrogen synthesis and inflammatory responses. Nevertheless, the mechanisms underlying the effects of cholesterol on endometriosis progression and immune response remain to be elucidated. Our research revealed that cholesterol accumulation in ectopic lesions acts as a crucial catalyst for the progression of endometriosis. Using a co-culture system, we simulated a cholesterol-abundant ectopic milieu and demonstrated cholesterol induced M2 macrophage polarization via the STAT6/PPARγ pathway, connecting cholesterol metabolism to immune response in endometriosis. Notably, cholesterol-induced M2 macrophage polarization accelerated the aggressive behavior of ectopic endometrial stromal cells (EESCs). Furthermore, we identified solute carrier family 25 member 1 (SLC25A1) as a pivotal target for regulating cholesterol metabolism in endometriosis, as it significantly upregulated in ectopic lesions and markedly increased intracellular and extracellular cholesterol content. In vitro and in vivo experiments revealed that cholesterol supplementation reversed the cellular and immune microenvironment alterations caused by SLC25A1 knockdown. Collectively, our results demonstrated that SLC25A1 upregulated the cholesterol metabolism in EESCs and mediated M2 macrophages polarization via the STAT6/PPARγ signaling pathway. Our study on the molecular mechanisms underlying cholesterol accumulation and function may provide potential targets and therapeutic strategies for endometriosis management.

Keywords:  Endometriosis; SLC25A1; cholesterol accumulation; macrophage polarization.

DOI:  https://doi.org/10.7150/ijbs.117146
Nat Commun. 2025 Dec 12. 16(1): 11034

Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma.

Zhou Lu, Huanchen Shi, Rongshan Gao, Chengjie Zhong, Wei Zhang, Jian Zhu, Jianhang Huang, Ronghua Liu, Yun Xing, Yiwei Chu, Haixiang Sun, Guoming Shi, Aiwu Ke, Jian Zhou, Jiabin Cai, Jia Fan, Pingting Gao, Cheng Huang.

Paraoxonase-1 (PON1) is specifically expressed in the liver and has crucial effects on various liver diseases. The functions and underlying mechanisms of PON1 in hepatocellular carcinoma (HCC) remain unclear. Here, we demonstrate that PON1 serves as a metabolic regulator to counteract regulatory T (Treg) cell-mediated immunosuppression, thereby suppressing HCC progression. Mechanistically, PON1 promotes Von Hippel-Lindau protein (VHL)-mediated ubiquitination and degradation of hypoxia-inducible factor alpha (HIF-1α), leading to attenuated lactic acid production and limited Treg cell accumulation in the HCC microenvironment. In clinical settings, higher PON1 expression is correlated with a better prognosis in patients with HCC. Recombinant PON1 protein (rPON1) effectively impeded tumor growth. Furthermore, enhancing Pon1 expression with quercetin sensitized HCC to anti-programmed death-1(PD-1) therapy in murine HCC. Our findings elucidate a role of PON1 in orchestrating lactic acid production to relieve immunosuppression and suppress HCC, paving the way for targeting PON1 as a therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-025-66168-y
Front Immunol. 2025 ;16 1719613

Radiation-induced eCIRP causes macrophage phagocytic dysfunction via mitochondrial impairment and ferroptosis.

Mian Zhou, Gaifeng Ma, Jingsong Li, Satoshi Yamaga, Max Brenner, Monowar Aziz, Ping Wang.

  Ionizing radiation causes immune dysfunction, increasing susceptibility to infection and mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) is released from cells during irradiation. This study investigates how radiation-induced eCIRP release causes macrophage phagocytic dysfunction via ferroptosis, with a focus on the role of mitochondrial dysfunction. Peritoneal macrophages were exposed to 10-Gy irradiation. eCIRP levels in the culture supernatants were assessed post-irradiation by ELISA. Ferroptosis was assessed by measuring lipid peroxidation and glutathione peroxidase 4 (GPX4) expression. Mitochondrial function was assessed using Mito stress assay in a Seahorse metabolic analyzer. Phagocytic activity was quantified by measuring the uptake of pHrodo-labeled E. coli. Our results demonstrated that 10-Gy irradiation induced ferroptosis in peritoneal macrophages. Markers of ferroptosis, lipid peroxidation, were significantly elevated, and GPX4 was significantly downregulated in a time-dependent manner on days 3 and 5 post-irradiation. We unveiled a strong time-dependent correlation between post-irradiation eCIRP release and the increases in ferroptosis and macrophage phagocytic dysfunction at days 3 and 5. Furthermore, radiation-induced eCIRP positively correlated with mitochondrial dysfunction, evidenced by marked reductions in basal and maximal respiration and ATP production, mirroring effects of direct eCIRP treatment. Crucially, the application of MFG-E8-derived oligopeptide 3 (MOP3), a novel opsonic eCIRP inhibitor, effectively cleared eCIRP, restoring mitochondrial function, reducing ferroptosis, and improving phagocytosis in irradiated macrophages. These findings establish that radiation-induced eCIRP release drives mitochondrial dysfunction and ferroptosis, thereby impairing macrophage phagocytosis. Targeting eCIRP offers a promising therapeutic strategy to enhance host defense following radiation exposure.

Keywords:  eCIRP; ferroptosis; ionizing radiation; macrophage; mitochondria; phagocytosis

DOI:  https://doi.org/10.3389/fimmu.2025.1719613
Front Immunol. 2025 ;16 1669054

DAMP-driven trained immunity: metabolic and epigenetic reprogramming in critical illness and chronic inflammation.

Han G Kim, Jaimar C Rincon, Philip A Efron, Robert Maile.

  Innate immune memory, traditionally underappreciated in contrast to adaptive immunity, is now recognized as a critical component of host defense, particularly in the context of sepsis and sterile inflammatory injury. Recent advances have identified a central role for metabolic and epigenetic reprogramming in driving trained immunity (TRIM), where monocytes, macrophages, and other innate cells develop enhanced or tolerized responses to secondary stimuli. This review synthesizes current knowledge of how damage-associated molecular patterns (DAMPs), including oxidized LDL, HMGB1, heme, urate crystals, and mitochondrial DNA, serve as potent inducers of immunometabolic rewiring, often through the mTOR/HIF-1α axis or alternative pathways such as SYK signaling. We highlight distinct epigenetic mechanisms, such as enhancer priming via H3K4me1/H3K27ac, and metabolic shifts like the Warburg effect, succinate accumulation, and fatty acid synthesis, that define the trained or tolerized states. Particular attention is given to the relevance of these mechanisms in the pathophysiology of sepsis, burns, trauma, and other critical illnesses where persistent DAMP exposure may sustain maladaptive inflammation or immunosuppression. We review data linking central (stem cell-level) and peripheral reprogramming to long-term immune dysfunction in various inflammatory disease models, and explore how DAMPs intersect with PAMPs to shape the immune trajectory. Finally, we identify pressing gaps in the field, including the need for standardized TRIM models, validated biomarkers of innate memory, and mechanistic clarity on mitochondrial DAMPs in immune tolerance. These insights provide a foundation for future therapeutic strategies aimed at modulating trained immunity to improve outcomes in critically ill patients.

Keywords:  DAMPs; epigenetics; innate immunity; innate training; trauma

DOI:  https://doi.org/10.3389/fimmu.2025.1669054
Clin Exp Immunol. 2025 Dec 09. pii: uxaf077. [Epub ahead of print]

Multiomics analysis of neutrophils in SLE: insights from adult and pediatric disease.

Grace Filbertine, Isobel Kynoch, Genna A Abdullah, Lucy Gill, Rudi Grosman, Marie M Phelan, Zoe McLaren, Tawatchai Deekajorndech, Direkrit Chiewchengchol, Nattiya Hirankarn, Helen L Wright.

Neutrophils contribute to systemic lupus erythematosus (SLE) pathogenesis through ROS and NET production, and increased apoptotic debris which causes autoantibody production and immune complex formation. These processes drive inflammation and tissue damage. The aim of this study was to perform integrated transcriptomic and metabolomic analyses comparing paediatric and adult SLE neutrophils. Adult (aSLE) and pediatric (jSLE) patient and healthy adult (HA) and juvenile (HJ) control neutrophils were subjected to RNAseq and 1H-NMR metabolomics. Univariate, multivariate and multiomics enrichment analyses were conducted in R and with Ingenuity Pathway Analysis (IPA). Transcriptomic analysis revealed distinct gene expression profiles. Adult and juvenile SLE neutrophils were enriched for genes regulating IFN-α/β signalling, neutrophil degranulation and NET signalling pathways (IPA, adj.p-value<0.01). Gene Ontology analysis revealed enrichment in cell cycle and interferon signalling in aSLE, and angiogenesis and tissue-specific development in jSLE. Metabolomic profiling identified distinct metabolic alterations in aSLE, with a greater complexity of metabolic changes in jSLE. Multivariate PLS-DA demonstrated group discrimination, particularly in aSLE (balanced accuracy 80%, sensitivity 80%). VIP>1 metabolites were enriched in taurine/hypotaurine and amino acid metabolism in aSLE. Integrating transcriptomic and metabolomic data strengthened IFN-α/β signalling, neutrophil degranulation and NET signalling (adj. p <0.001). Additional metabolic pathways uniquely down-regulated in aSLE included glutamate and glutamine metabolism, nucleotide biosynthesis and tryptophan catabolism (adj.p<0.01). In summary, neutrophils from SLE patients, especially in jSLE, displayed complex transcriptomic and metabolic profiles, with aberrant IFN responses and neutrophil activation.

DOI: https://doi.org/10.1093/cei/uxaf077
Nat Commun. 2025 Dec 12. 16(1): 11104

Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.

Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.

DOI: https://doi.org/10.1038/s41467-025-66708-6
Nat Commun. 2025 Dec 12. 16(1): 11088

Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.

Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.

Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.

DOI: https://doi.org/10.1038/s41467-025-66042-x
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2507422122

Glomerular endothelial cells eliminate nicotinamide adenine dinucleotide to instruct CD103+ T cells in human lupus nephritis.

Li Jia, Mengdi Liu, Huiyan Ji, Jiaxin Lei, Danhua Su, Lingyi Li, Ting Liu, Fenghong Yuan, Lin Xu, Qinghua Cao, Huimin Zhang, Zhenke Wen.

  Lupus nephritis (LN), which is characterized by the accumulation of DNA-containing immune complexes (ICs), is the leading cause of death in patients with systemic lupus erythematosus (SLE). While growing evidence highlights the central role of CD103+ T cells in shaping the immune landscape of regional tissues, mechanisms driving the cell differentiation in LN remain largely unexplored. In this study, we identified an increased frequency of CD4+CD103+ T cells within the kidneys of SLE patients. Importantly, glomerular endothelial cells (ECs) from human LN tissues were found to promote the differentiation of CD4+CD103+ T cells by upregulating B lymphocyte-induced maturation protein 1 (Blimp-1). Genetic knockdown of Blimp-1 in CD4+ T cells resulted in a reduced frequency of renal CD4+CD103+ T cells and alleviated LN in humanized SLE chimeras. Mechanistically, LN-associated ECs, triggered by circulating DNA from SLE patients, exhibited elevated CD38 expression via the cGAS-STING signaling pathway. This facilitated the transfer of CD38 into CD4+ T cells through an exosome-dependent mechanism, leading to the depletion of nicotinamide adenine dinucleotide (NAD+) levels in CD4+ T cells. The resulting NAD+ depletion impaired the PARP1-mediated ADP-ribosylation of early growth response protein 1 (EGR1), which, in turn, enhanced Blimp-1 transcription and promoted CD103+ T cell differentiation. Targeting the cGAS/STING-CD38-EGR1 axis effectively reduced renal CD103+ T cell accumulation and inhibited LN progression in humanized SLE chimeras. Thus, ECs facilitate NAD+ depletion to drive CD103+ T cell differentiation, presenting a cellular mechanism underlying LN pathogenesis and a potential therapeutic target for the clinical management of human LN.

Keywords:  CD103+ T cell; Lupus nephritis; endothelial cell

DOI:  https://doi.org/10.1073/pnas.2507422122
Nat Commun. 2025 Dec 11. 16(1): 11106

Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.

Konstantinos Makris, Vlera Fonda, Fania Feby Ramadhani, Lina Fadel, Morgane Davezac, Bertrand Payet, Ioannis K Deligiannis, Liwei Zhang, Teresa Horn, Laura Heimerl, Céline Jouffe, Marjolein Heddes, Celia P Martinez-Jimenez, Fabiana Quagliarini, N Henriette Uhlenhaut.

Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.

DOI: https://doi.org/10.1038/s41467-025-67228-z
Cell Metab. 2025 Dec 10. pii: S1550-4131(25)00493-0. [Epub ahead of print]

Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade.

Ming-Ming Wu, Yan-Chao Yang, Zhi-Qiang Hu, Jie-Yu Chang, Han Xiao, Chang Miao, Bo-Wen Zhang, Zhi-Xi He, Di Zhu, Yu-Ran Duan, Shuo Wang, Jian-Yu Liu, Zhan-Peng Guo, Yu Sun, Dan-Yang Liu, Miao Yu, Yue Zhang, Jian-Jun Mao, Shuai Jiang, Bing-Kun Zhang, Zhu Mei, Jun Gao, Chen Liang, Qiu-Shi Wang, Chang-Jiang Yu, Dan Zhao, Cheng-Hui Yan, Yue Li, Zhen-Wei Pan, Zheng Chen, Da-Qian Xu, Tong Liu, Yong Ji, Zhi-Ren Zhang.

  Immune checkpoint inhibitor (ICI) therapies increase the risk of metabolic syndrome; the underlying mechanisms remain elusive. We show that an anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, augmenting the susceptibility of mice to high-fat diet (HFD)-induced obesity and systemic metabolic disorders. Mechanistically, lipopolysaccharide (LPS) activates Unc-51-like autophagy activating kinase 1 (ULK1) in a mammalian target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress endoplasmic reticulum (ER) stress-mediated inflammatory responses. Suppressing IRE1α alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 at the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 may provide a new rationale for combating ICI therapy- and HFD-induced metabolic diseases.

Keywords:  ER stress; IRE1α; macrophage PD-1; metabolic diseases; obesity

DOI:  https://doi.org/10.1016/j.cmet.2025.11.009
Front Pharmacol. 2025 ;16 1689575

Carnosine as a protective metabolic mediator in inflammatory lung injury by inhibiting macrophage infiltration and M1-like polarization.

Lianjie Ruan, Dekai Lin, Binqin Lin, Qingqing Zhan, Lili Zheng, Dandan Lin, Yaoning Zhuang, Yiming Zeng.

   Background: Inflammatory lung injury is a common pathological feature of pneumonia caused by various infectious and non-infectious agents. However, metabolic regulators that can mitigate inflammation and immune cell infiltration in diverse lung injury models remain poorly understood.
Methods: Using targeted metabolomic profiling of lung tissues collected on day 5 from two distinct murine models of lung inflammation-lipopolysaccharide (LPS)-induced and papain-induced-we identified carnosine as a commonly downregulated metabolite in both models. To evaluate its therapeutic potential, we administered exogenous carnosine in both models and assessed its effects on body weight, inflammatory cytokine expression, and histopathological changes.
Results: Carnosine supplementation significantly improved body weight maintenance, reduced the expression of pro-inflammatory cytokines, and attenuated histological lung damage in both LPS- and papain-induced lung injury models. Flow cytometry analysis revealed that carnosine treatment markedly decreased pulmonary infiltration of macrophages and neutrophils. Multiplex immunofluorescence further demonstrated a significant reduction of macrophage accumulation in the peribronchial regions of the lung following carnosine administration. In vitro experiments using bone marrow-derived macrophages (BMDMs) confirmed that carnosine effectively suppressed LPS-induced inflammatory responses and inhibited polarization toward the M1-like macrophage phenotype.
Conclusion: Our findings identify carnosine as a protective metabolic mediator in inflammatory lung injury and demonstrate its capacity to alleviate pulmonary inflammation by modulating innate immune cell recruitment and macrophage polarization. These results highlight the translational potential of carnosine as a therapeutic agent for treating inflammatory lung diseases.

Keywords:  carnosine; immune homeostasis; inflammation; lung injury; metabolomic profiling

DOI:  https://doi.org/10.3389/fphar.2025.1689575