bims-imicid 2025-08-10 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–08–10
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.
Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense.
Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.
Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.
Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
Endothelial-Derived CCL7 Promotes Macrophage Polarization and Aggravates Septic Acute Lung Injury via CCR1-Mediated STAT1 Succinylation.
Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect.
Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.
Glycogen shepherd guides the hidden trail of pentose phosphate pathway.
Metabolic landscape uncovers remodeling of T cell immunity affected by fatty acid desaturase in Parkinson's disease at single-cell resolution.
Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria.
Disrupted macrophage metabolic adaptation and function drive senescence-induced decline in vertebrate regeneration.
NF-κB inactivation in myeloid cell leads to reprogramming of whole-body energy metabolism in response to high-fat diet.
Spatial organization of pulmonary type 2 inflammation by a macrophage-derived cholesterol metabolite.
Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution.
Non-invasive visualisation of long-lasting brain metabolic alterations in murine pseudo-infection model using parahydrogen-polarised [1-13C] pyruvate MRI.
Lipid metabolism and neuroinflammation: What is the link?
Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.
Macrophages say NO to nucleotide synthesis and salvage instead.
CSF1R regulates monocyte subset differentiation and intracellular metabolism.
FABP7-mediated lipid-laden macrophages drive the formation of pre-metastatic niche and liver metastasis.
Butyrate-producing gut bacterium Faecalibacterium prausnitzii protects against bacterial pneumonia.
Inosine boosts infant antiviral immunity.
A prometabolite strategy inhibits cardiometabolic disease in an ApoE-/- murine model of atherosclerosis.
Toxoplasma gondii-induced host's high secretion of 25-hydroxycholesterol for immunoprotection.

Cell Metab. 2025 Jul 30. pii: S1550-4131(25)00333-X. [Epub ahead of print]

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.

Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Nicole M Foy, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.

  Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8+ T cell responses in vivo.

Keywords:  CD8(+) T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.07.006
Nat Metab. 2025 Aug 04.

Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.

Steven V John, Gretchen L Seim, Billy J Erazo-Flores, James A Votava, Uzziah S Urquiza, Nicholas L Arp, John Steill, Jack Freeman, Lauren N Carnevale, Isaiah Roberts, Xin Qing, Stuart A Lipton, Ron Stewart, Laura J Knoll, Jing Fan.

During an immune response, macrophages specifically reprogramme their metabolism to support functional changes. Here, we revealed that nucleotide metabolism is one of the most significantly reprogrammed pathways upon classical activation. Specifically, de novo synthesis of pyrimidines is maintained up to uridine monophosphate, but blocked at cytidine triphosphate and deoxythymidine monophosphate synthesis; de novo synthesis of purines is shut off at the last step (catalysed by AICAR transformylase/IMP cyclohydrolase, ATIC), and cells switch to increased purine salvage. Nucleotide degradation to nitrogenous bases is upregulated but complete oxidation of purine bases (catalysed by xanthine oxidoreductase, XOR) is inhibited, diverting flux into salvage. Mechanistically, nitric oxide was identified as a major regulator of nucleotide metabolism, simultaneously driving multiple key changes, including the transcriptional downregulation of Tyms and profound inhibition of ATIC and XOR. Inhibiting purine salvage using Hgprt knockout or inhibition alters the expression of many stimulation-induced genes, suppresses macrophage migration and phagocytosis, and increases the proliferation of the intracellular parasite Toxoplasma gondii. Together, these results thoroughly uncover the dynamic reprogramming of macrophage nucleotide metabolism upon classical activation and elucidate the regulatory mechanisms and functional significance of such reprogramming.

DOI: https://doi.org/10.1038/s42255-025-01337-3
bioRxiv. 2025 Jul 26. pii: 2025.07.23.664455. [Epub ahead of print]

Human iPSC derived alveolar macrophages reveal macrophage subtype specific functions of itaconate in M. tuberculosis host defense.

Adam Krebs, Tomi Lazarov, Anthony Reynolds, Kimberly A Dill-McFarland, Abigail Xie, James Bean, Muxue Du, Olivier Levy, John Buglino, Aaron Zhong, Anna-Lena Neehus, Stephanie Boisson-Dupuis, Jean-Laurent Casanova, Elouise E Kroon, Marlo Möller, Thomas R Hawn, Ting Zhou, Lydia W S Finley, Marc Antoine Jean Juste, Dan Fitzgerald, Frederic Geissmann, Michael S Glickman.

Mycobacterium tuberculosis (Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to M. tuberculosis (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown. Here, we investigated the role of itaconate in human iPSC-derived macrophages, either induced by GM-CSF to resemble alveolar macrophages (AM-Like cells), or treated with M-CSF to generate control macrophages (MCDM cells). Both types of human macrophages produce substantially less itaconate than mouse macrophages and AM-Ls produced 4-fold less itaconate than MCDMs. Surprisingly, ACOD1 deficient AM-L macrophages, but not MCDM macrophages, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb induced inflammatory response in MCDMs, but not AM-L macrophages, affecting both the Type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to TB, with distinct roles in different macrophage subsets. These results also show that genetically tractable hiPSC-derived macrophages are a robust and versatile model to dissect cellular host pathogen interactions.

DOI: https://doi.org/10.1101/2025.07.23.664455
Immunity. 2025 Jul 29. pii: S1074-7613(25)00321-8. [Epub ahead of print]

Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.

Samuel E Weinberg, Navdeep S Chandel.

Mitochondria are key regulators of immune cell function, going beyond their traditional role in ATP and metabolite production to support anabolic processes and act as hubs for intracellular signaling. A key aspect of this signaling function is the production of mitochondrial reactive oxygen species (mtROS), which act as critical second messengers in both adaptive and innate immune regulation. Immune cells maintain an optimal concentration of mtROS to maintain physiological responses, and excessive or lack of mtROS production contributes to chronic inflammation, autoimmunity, and cancer. Here, we review the molecular mechanisms controlling mtROS production and detoxification, their role in shaping macrophage and T cell fate and function, and their implications for disease pathogenesis.

DOI: https://doi.org/10.1016/j.immuni.2025.07.012
Nat Cell Biol. 2025 Aug 08.

Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.

Xian Du, Wenyan Li, Guiying Li, Chenyue Guo, Xuyi Tang, Rujuan Bao, Runchang Li, Haiyan Huang, Shuiyu Xu, Xiaoyan Yu, Qiaoqiao Han, Jie Wan, Song Li, Jiayuan Sun, Ren Zhao, Youqiong Ye, Qiang Gao, Zhi-Yu Ni, Xingang Cui, Qiang Zou.

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.

DOI: https://doi.org/10.1038/s41556-025-01716-8
Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00300-6. [Epub ahead of print]37(8): 1630-1632

Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.

Eugenio Barone, D Allan Butterfield.

Insulin resistance is a risk factor for Alzheimer's disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.

DOI: https://doi.org/10.1016/j.cmet.2025.06.005
Adv Sci (Weinh). 2025 Aug 04. e06209

Endothelial-Derived CCL7 Promotes Macrophage Polarization and Aggravates Septic Acute Lung Injury via CCR1-Mediated STAT1 Succinylation.

Xue Li, Yuqin Long, Yunxi Zhu, Jiahui Gu, Ping Zhou, Changhong Miao.

  Acute lung injury (ALI) is a significant complication of sepsis, wherein the interaction between pulmonary vascular endothelial cells and immune cells plays a pivotal role in the pathogenesis. In this study, it is demonstrated that secretion of chemokine C-C motif ligand 7 (CCL7) by endothelial cells (ECs) induces metabolic reprogramming and M1 polarization of C-C motif chemokine receptor 1-positive (CCR1⁺) macrophages. It is noteworthy that mice with specific inhibition of endothelial-derived CCL7 exhibit reduced severity of septic ALI, underscoring the critical role of CCL7 in the progression of sepsis. Mechanistically, activation of the CCL7-CCR1 axis enhances STAT1 succinylation through upregulation of KAT2A expression, leading to increased STAT1 binding to the promoter of glycolytic genes in macrophages. This epigenetic regulation modulates metabolic reprogramming and M1 polarization of macrophages, thereby driving inflammatory cascades in septic ALI. Furthermore, in sepsis models, Ccr1-knockout (Ccr1-KO) mice demonstrate attenuated lung inflammation and decreased mortality, highlighting the therapeutic potential of targeting the CCL7-CCR1 axis for the treatment of septic ALI. Collectively, findings provide novel insights into the metabolic reprogramming of macrophages and identify the CCL7-CCR1 axis as a promising therapeutic target for septic ALI.

Keywords:  CCL7; glycolysis; macrophage; sepsis; succinylation

DOI:  https://doi.org/10.1002/advs.202506209
Res Sq. 2025 Jul 29. pii: rs.3.rs-7077811. [Epub ahead of print]

Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect.

Bhupesh Kumar Prusty, Claudia Hollmann, Eun Chan Park, Zheng Liu, Faye Nourollahi, Georgy Nikolayshvili, Jonathan Dietz, Emils Bašēns, Mehul Vora, Trushnal Waghmare, Tongbin Li, Fabian Imdahl, Christopher Rongo.

Multiple mechanisms of immunity must be coordinated to defend against a comprehensive range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we employed systems biology approaches to understand the organization of human immune cells at the single-cell level, as well as their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 induced pro-inflammatory pathways in M1 and M2c macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, and improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of mechanism. Our work demonstrates that a drug that remodels mitochondria and metabolism can shape the immune cell repertoire, which could aid the development of more effective antimicrobials and prevent the emergence of drug-resistant pathogens.

DOI: https://doi.org/10.21203/rs.3.rs-7077811/v1
PLoS Pathog. 2025 Aug;21(8): e1013291

Inactivation of branched-chain amino acid uptake halts Staphylococcus aureus growth and induces bacterial quiescence within macrophages.

Adriana Moldovan, Ronald S Flannagan, Marcel Rühling, Kathrin Stelzner, Clara Hans, Kerstin Paprotka, Tobias C Kunz, David E Heinrichs, Thomas Rudel, Martin J Fraunholz.

Staphylococcus aureus is a notorious human pathogen that thrives in macrophages. It resides in mature phagolysosomes, where a subset of the bacteria eventually begin to proliferate. How S. aureus acquires essential nutrients, such as amino acids, for growth in this niche is poorly understood. Using a long-term primary human macrophage infection model, we show that branched-chain amino acid (BCAA) uptake mediated by the major transporter BrnQ1 is required by S. aureus for intracellular replication in macrophages and we provide mechanistic insight into the role of BCAAs in the success of intracellular S. aureus. Loss of BrnQ1 function renders intracellular S. aureus non-replicative and non-cytotoxic. The defective intracellular growth of S. aureus brnQ1 mutants can be rescued by supplementation with BCAAs or by overexpression of the BCAA transporters BrnQ1 or BcaP. Inactivation of the CodY repressor rescues the ability of S. aureus brnQ1 mutants to proliferate intracellularly independent of endogenous BCAA synthesis but dependent on BcaP expression. Non-replicating brnQ1 mutants in primary human macrophages become metabolically quiescent and display aberrant gene expression marked by failure to respond to intraphagosomal iron starvation. The bacteria remain, however, viable for an inordinate length of time. This dormant, yet viable bacterial state is distinct from classical persisters and small colony variants.

DOI: https://doi.org/10.1371/journal.ppat.1013291
Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00329-8. [Epub ahead of print]37(8): 1633-1635

Glycogen shepherd guides the hidden trail of pentose phosphate pathway.

Lin Wang, Kaili Ma, Lianjun Zhang, Ping-Chih Ho.

In a recent Molecular Cell study,1 Zhou et al. elucidated how glycogenolysis-derived glucose-1-phosphate mediates source-specific routing of glucose-6-phosphate into the pentose phosphate pathway through allosteric activation of glucose-6-phosphate dehydrogenase and liquid-liquid phase separation-mediated metabolic compartments. This compartmentalized distribution enables efficient reduced nicotinamide adenine dinucleotide phosphate (NADPH) generation from glycogenolytic flux, promoting Tm cell persistence by maintaining redox homeostasis.

DOI: https://doi.org/10.1016/j.cmet.2025.07.002
BMC Biol. 2025 Aug 06. 23(1): 245

Metabolic landscape uncovers remodeling of T cell immunity affected by fatty acid desaturase in Parkinson's disease at single-cell resolution.

Shi Yan, Xue Zhao, Yao Si, Xinyu Zhang, Di Wang, Lifen Yao, Linlin Sun.

   BACKGROUND: Peripheral activated T cells cross the blood-brain barrier, partake in neuroinflammation, and induce dopaminergic neuron degeneration through characteristics such as cell adhesion and immune response in Parkinson's disease (PD). Metabolic activity, which can regulate and be regulated by cellular signaling pathways, has a profound impact on the differentiation and function of T cells. However, a characterization of T-cell metabolic heterogeneity at single-cell resolution in PD is still lacking. Here, combining metabolic gene expression profiling and pathway activity algorithm, we studied the metabolic programs in PD-associated T cells.
RESULTS: Cytotoxic T cells (CTLs) with adhesive properties dominated the proportion in PD patients based on the distribution of T cell types at single-cell resolution. The unsaturated fatty acid (UFA) biosynthetic process was found to be the pivotal contributor to CTLs' metabolic features distinct from other cell types. Meanwhile, the upregulation of UFA biosynthetic process strongly correlated with immunologic activity in CTLs. Additionally, we revealed that fatty acid desaturases became the critical factor in determining CTLs' metabolic heterogeneity according to the differentiation of T cell lineage and the high expression of metabolic genes in PD. Subsequent fatty acid desaturases adjustments mediated crosstalk with CTLs' immunity, suggesting a potential target for regulating neuroinflammation in PD condition.
CONCLUSIONS: This analysis decoded the activation of T cells from another perspective, where PD-associated CTLs were metabolically reprogrammed to interact with the immune system, for in-depth insights into the immune characteristics of PD.

Keywords:  Metabolic reprogramming; Parkinson’s disease; T cells; Unsaturated fatty acid biosynthetic process; scRNA-seq

DOI:  https://doi.org/10.1186/s12915-025-02358-w
bioRxiv. 2025 Aug 01. pii: 2025.08.01.668058. [Epub ahead of print]

Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria.

Kent L Marshall, Ethan Meadows, Alan Mizener, John M Hollander, Christopher P Cifarelli.

Glioblastoma (GBM) exhibits profound plasticity, enabling adaptation to fluctuating microenvironmental stressors such as hypoxia and nutrient deprivation. However, this metabolic rewiring also creates subtype-specific vulnerabilities that may be exploited therapeutically. Here, we investigate whether mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria alters the metabolic architecture of GBM cells and modulates their response to ionizing radiation. Using a cell-penetrating peptide-mediated delivery system, we successfully introduced mitochondria into two mesenchymal-subtype GBM cell lines, U3035 and U3046. Transplanted cells exhibited enhanced mitochondrial polarization and respiratory function, particularly in the metabolically flexible U3035 line. Bioenergetic profiling revealed significant increases in basal respiration, spare respiratory capacity, and glycolytic reserve in U3035 cells post-transplantation, whereas U3046 cells showed minimal bioenergetic augmentation. Transcriptomic analyses using oxidative phosphorylation (OXPHOS) and glycolysis gene sets confirmed these functional findings. At baseline, U3035 cells expressed high levels of both glycolytic and OXPHOS genes, while U3046 cells were metabolically suppressed. Following radiation, U3035 cells downregulated key OXPHOS and glycolysis genes, suggesting metabolic collapse. In contrast, U3046 cells transcriptionally upregulated both pathways, indicating compensatory adaptation. These results identify and establish mitochondrial transplantation as a metabolic priming strategy that sensitizes adaptable GBM subtypes like U3035 to therapeutic stress by inducing bioenergetic overextension. Conversely, rigid subtypes like U3046 may require inhibition of post-radiation metabolic compensation for effective targeting. Our findings support a novel stratified approach to GBM treatment which integrates metabolic subtype profiling with bioenergetic modulation.

DOI: https://doi.org/10.1101/2025.08.01.668058
Theranostics. 2025 ;15(15): 7308-7326

Disrupted macrophage metabolic adaptation and function drive senescence-induced decline in vertebrate regeneration.

Audrey Barthelaix, Claudia Terraza-Aguirre, Yalén Del Río-Jay, Candice Bohaud, Jérémy Salvador, Marie Morille, Miguel Godinho Ferreira, Christian Jorgensen, Farida Djouad.

   RATIONALE: Senescent cells accumulate with age and contribute to impaired tissue regeneration. Here, we developed a senescence-accelerated zebrafish (SAZ) model, characterized by accelerated senescence-like traits and a significant impairment in caudal fin regeneration.
METHODS: To investigate the underlying mechanisms of this regenerative defect, we employed a multifaceted approach. We used transgenic zebrafish lines for 4-D tracking of macrophage subsets during regeneration and performed parabiosis to assess the impact of systemic factors. Then, we isolated macrophages by FACS-sorting for a comprehensive transcriptomic study using RT-qPCR, enabling us to analyze both senescence markers and metabolic markers specifically within SAZ macrophages. Furthermore, we conducted phagocytosis assays to evaluate macrophage function. To explore the role of specific metabolic pathways, we used pharmacological treatments with oligomycin and galloflavin.
RESULTS: Our findings revealed that the reduced regenerative potential in SAZ was partly attributable to an impaired macrophage response during regeneration. We observed higher expression of the senescence marker cdkn2a/b in SAZ macrophages, which correlated with their reduced ability to polarize into a pro-inflammatory phenotype and exert efficient phagocytosis. These observations were linked to a significant downregulation of ldha, a key enzyme in lactate production, specifically within SAZ macrophages at 24 hours post-amputation. Enhancing anaerobic glycolysis in the SAZ model during early regeneration restored ldha expression, normalized macrophage activation dynamics, and ultimately rescued caudal fin regeneration. This rescue was entirely abolished by co-treatment with galloflavin, a direct inhibitor of LDH isoforms A and B, thereby underscoring the critical role of lactate metabolism in the regenerative process.
CONCLUSION: Collectively, our findings demonstrate that senescence impairs regeneration by altering macrophage metabolic adaptation and functions, providing novel insights into the interplay between aging and regenerative capacity.

Keywords:  macrophage; metabolism; phagocytosis; polarization; regeneration; senescence

DOI:  https://doi.org/10.7150/thno.111352
Cell Death Discov. 2025 Aug 05. 11(1): 367

NF-κB inactivation in myeloid cell leads to reprogramming of whole-body energy metabolism in response to high-fat diet.

Xianghong Wang, Zhe Yang, Xin Ye, Owen P McGuinness, Hengwen Yang, Hongyun Lu, Jianping Ye.

Energy metabolism is subject to reprogramming in the body upon bacterial or virus infection. It is generally believed that immune cells sense the stress signals of infection to mediate the reprogramming of whole-body energy metabolism. However, the key molecules required for the immune cell function remain to be identified. In this study, we addressed the issue by examining the energy metabolism in Lyz2-p65-KO mice, in which p65 (RelA) gene is inactivated in myeloid cells. On Chow diet, the p65-KO mice exhibited no difference to the wild type mice in the energy metabolism. On a high fat diet (HFD), the KO mice gained less adipose tissue and body weight for improved insulin sensitivity and blood lipids along reduction in pro-inflammatory cytokine. This was observed with more energy loss in feces. The KO mice showed a reduction in metabolic rate after LPS challenge for accelerated decrease of oxygen consumption. They had a high mortality rate in the septic shock model with less elevation of serum pro-inflammatory cytokines and more elevation of anti-inflammatory cytokines. In vitro, the KO macrophages expressed less pro-inflammatory cytokines in response to stimulation by palmitic acid, IL-1β and TNF-α. In conclusion, the data suggest that p65 is a key molecule in myeloid cells to mediate the reprogramming of energy metabolism under stress conditions of HFD feeding.

DOI: https://doi.org/10.1038/s41420-025-02659-7
bioRxiv. 2025 Aug 01. pii: 2025.07.29.666625. [Epub ahead of print]

Spatial organization of pulmonary type 2 inflammation by a macrophage-derived cholesterol metabolite.

Yufan Zheng, Hannah E Dobson, Makheni Jean Pierre, Lilly LeBlanc, Chinaemerem U Onyishi, Dominic P Golec, Nathan Carrillo, Anshu Deewan, Claudia A Rivera, Eduard Ansaldo, Eric V Dang.

Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (T H 2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produce 25-hydroxycholesterol, which is converted into the oxysterol 7α,25-dihydroxycholesterol to attract GPR183-expressing T H 2 cells into infectious lesions. This T H 2 positioning suppresses interferon-γ responsiveness in inflammatory Ly6C⁺ macrophages, promoting fungal persistence. Disruption of this axis via T H 2-specific GPR183 deletion restores type 1 macrophage activation and enhances fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.

DOI: https://doi.org/10.1101/2025.07.29.666625
Nat Metab. 2025 Aug 04.

Lactate signalling leads to aggregation of immune-inflammatory hotspots and SLC5A12 blockade promotes their resolution.

Michelangelo Certo, Elena Pontarini, Sebastian G Gilbert, Ronny Schmidt, Jason D Turner, Davide Lucchesi, Daria Apostolo, Giulia Cavallaro, Charlotte G Smith, Serena Colafrancesco, Joana Campos, Saba Nayar, Christoph Schröder, Benjamin A Fisher, Fabian Spill, Michele Bombardieri, Claudio Mauro.

Ectopic lymphoid structures (ELS) are aggregates of lymphoid cells that often form within inflamed tissues in patients with autoimmune diseases, cancer, infectious diseases and cardiovascular conditions. These structures drive B cell maturation into memory B cells and plasma cells through B cell and T cell co-stimulation, and their role in pathogenesis is increasingly recognized. Understanding how ELS develop and persist in inflamed tissues is essential for elucidating the pathogenesis and treatment responses in diseases in which they have a prominent role. Here we show that metabolic pathways and specific metabolites, in particular lactate, are master regulators of ELS organization in Sjögren's disease (SjD), the second-most common autoimmune rheumatic disease. Furthermore, inhibiting lactate uptake by lactate transporters, specifically by SLC5A12 blockade, represents a previously unappreciated checkpoint in autoimmune inflammatory diseases. This approach results in multidimensional pro-resolution effects, including reduced inflammatory cytokine levels, enhanced T cell egress from inflamed sites and diminished T cell and B cell areas and their segregation within ELS.

DOI: https://doi.org/10.1038/s42255-025-01331-9
Discov Nano. 2025 Aug 06. 20(1): 128

Non-invasive visualisation of long-lasting brain metabolic alterations in murine pseudo-infection model using parahydrogen-polarised [1-13C] pyruvate MRI.

Hayate Tomiyama, Masaki Yamasaki, Takayuki Isagawa, Norihiko Takeda, Takuya Hashimoto, Hiroshi Hirata, Shingo Matsumoto.

  Long-lasting neurological issues, including cognitive impairment, anxiety, and depression, that persist after recovery from acute inflammatory diseases, such as infections, have become a significant social problem, particularly following the coronavirus disease 2019 pandemic. Various diagnostic techniques and biomarkers have been explored to objectively evaluate brain symptoms associated with infection-induced local or systemic inflammatory responses (i.e. immune fatigue); however, their detection capabilities remain limited. Here we investigated whether magnetic resonance imaging (MRI) combined with a quantum-sensed molecule, parahydrogen-polarised [1-13C] pyruvate, could detect persistent brain metabolic alterations in a murine pseudo-infection model induced by polyinosinic-polycytidylic acid (Poly(I: C)), a Toll-like receptor 3 ligand. Significant alterations in brain pyruvate metabolism favouring glycolysis were observed in both the acute and late phases of the pseudo-infection model, with a 12.7% and 2.5% decrease in bicarbonate flux, and a 58.4% and 32.2% increase in lactate flux on day 3 and week 2, respectively. These brain metabolic changes were accompanied by diminished dopamine signal markers in the striatum and nigra/ventral tegmental areas and reduced spontaneous nocturnal locomotor activity. A biochemical analysis of energy metabolic markers consistently supported the reprogramming of brain glucose metabolism, showing the suppression of oxidative phosphorylation during the acute phase and promotion of glycolysis during the late phase of Poly(I: C) treatment. Hyperpolarised 13C MRI of pyruvate metabolism is a promising non-invasive imaging biomarker for brain issues during the late phase of systemic infections and other neurodegenerative and psychiatric diseases, particularly in conditions lacking discernible morphological abnormalities.

Keywords:  Brain metabolism; Hyperpolarised 13C MRI; Immune fatigue; Infection; PHIP; Quantum sensing

DOI:  https://doi.org/10.1186/s11671-025-04304-9
J Exp Med. 2025 Sep 01. pii: e20241232. [Epub ahead of print]222(9):

Lipid metabolism and neuroinflammation: What is the link?

Vini Tiwari, Mikael Simons.

Lipid metabolism is central to host defense by supporting and modulating immune cell function. Immune signaling pathways control anabolic lipid processes to drive membrane synthesis and produce bioactive lipid mediators during activation. In turn, metabolic states profoundly influence immune signaling, particularly during the resolution of inflammation. Emerging evidence highlights a dynamic interplay between lipid metabolism and neuroinflammation. A striking example is the intrinsic lipoprotein system of the central nervous system, which undergoes profound changes during pathology, with lipoproteins serving not only in lipid transport but also as immune modulators and as contributors to disease tolerance. Importantly, major neurodegenerative diseases are genetically linked to disruptions in lipid metabolism. Deciphering this complex cross talk may provide opportunities for novel therapies targeting neuroinflammatory and neurodegenerative disorders.

DOI: https://doi.org/10.1084/jem.20241232
Cancer Res. 2025 Aug 07.

Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.

Mohamed Faisal Kassir, Han Gyul Lee, Natalia V Oleinik, Wyatt Wofford, Chase Walton, Firdevs Cansu Atilgan, Alhaji H Janneh, Paramita Chakraborty, Kubra Calisir, Elif Percin, Silvia G Vaena, Kalyani Sonawane, Ashish Deshmukh, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Ozgur Sahin, Shikhar Mehrotra, Besim Ogretmen.

Alzheimer's disease (AD) patients have a decreased incidence of cancer., with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD compared to AD patients. Here, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T-cells, improving their anti-tumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer (ACT)-based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T-cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving anti-tumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T-cells, enhancing their anti-tumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched AD patients. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance anti-tumor functions.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4740
Nat Metab. 2025 Aug 04.

Macrophages say NO to nucleotide synthesis and salvage instead.

Eloïse Marques, Dylan G Ryan.

DOI: https://doi.org/10.1038/s42255-025-01322-w
bioRxiv. 2025 Jul 21. pii: 2025.07.17.665275. [Epub ahead of print]

CSF1R regulates monocyte subset differentiation and intracellular metabolism.

Alexandre Gallerand, Johanna Merlin, Zakariya Caillot, Chloé Delaby, Elisa Bord, Jichang Han, Bastien Dolfi, Alexia Castiglione, Sacha Grenet, Maxime Franceschini, Gisèle Jarretou, Fairouz N Zair, Evy Boré, Florian Tuffin, David Dombrowicz, Rodolphe R Guinamard, Gwendalyn J Randolph, Adeline Bertola, Patrick Auberger, Arnaud Jacquel, David A Hume, Jesse W Williams, Marc Bajénoff, Jaap G Neels, Stoyan Ivanov.

Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6C high ) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6C low ) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6C low monocytes in part by blunting differentiation of Ly6C high monocytes. Based upon lineage-specific deletion of GFPT1 (Glutamine-Fructose-6-Phosphate Transaminase 1), the hexosamine biosynthetic pathway (HBP) is identified as a novel regulator of CSF1R expression and monocyte subset diversity. Our findings provide new insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.

DOI: https://doi.org/10.1101/2025.07.17.665275
Int J Biol Sci. 2025 ;21(10): 4388-4409

FABP7-mediated lipid-laden macrophages drive the formation of pre-metastatic niche and liver metastasis.

Shaowan Xu, Xin Peng, Zhenfang Wang, Chenchen Le, Xiangkun Wu, Zhicheng Zeng, Sisi Zeng, Ceng Zhang, Mingxing Qiu, Xin Zou, Hongxia Zhang, Feifei Wang, Wei Kang, Yanqing Ding, Li Liang.

  Abnormal metabolism processes play a crucial role in the establishment of the pre-metastatic niche (PMN) and the subsequent metastasis to distant organs. However, the precise mechanisms underlying the lipid metabolic reprogramming of macrophages within the liver PMN remain elusive. In this study, we observed an upregulation of fatty acid-binding protein 7 (FABP7) in liver macrophages, which resulted in the accumulation of lipid droplets (LDs) within the PMN of colorectal cancer and pancreatic ductal adenocarcinoma. This accumulation was found to be mediated by the HIF-1α-induced expression of FABP7, which in turn enhanced DGAT1 activity in these macrophages. Furthermore, FABP7-induced lipid-laden macrophages were observed to deliver lipids to CD8+ T and tumor cells via exosomes. This process led to CD8+ T cell dysfunction and increased tumor cell proliferation through metabolic reprogramming. Importantly, genetic knockout or pharmacological inhibition of FABP7 reduced liver metastasis. Our findings reveal a novel mechanism involving FABP7-mediated LD in macrophages that contributes to liver PMN formation and metastasis. This suggests that targeting FABP7 may offer prognostic and therapeutic potential in addressing liver metastasis.

Keywords:  fatty acid binding protein 7; macrophage; metabolic reprogramming; metastasis; pre-metastatic niche

DOI:  https://doi.org/10.7150/ijbs.110750
Eur Respir J. 2025 Aug 07. pii: 2402208. [Epub ahead of print]

Butyrate-producing gut bacterium Faecalibacterium prausnitzii protects against bacterial pneumonia.

Robert F J Kullberg, Christine C A van Linge, Alex F de Vos, Xanthe Brands, Thi Phuong Nam Bui, Joe M Butler, Daniël R Faber, Aswin Verhoeven, René M van den Wijngaard, Wouter J de Jonge, Max Nieuwdorp, Tom van der Poll, Bastiaan W Haak, W Joost Wiersinga.

BACKGROUND: Gut microbiota play a protective role against pneumonia in mice, probably by producing the immunomodulatory short-chain fatty acid butyrate. Yet, butyrate has limited potential for clinical use due to its challenging handling in practice. We performed mouse experiments and translational analyses to determine whether butyrate-producing gut commensals, Faecalibacterium prausnitzii and Anaerobutyricum soehngenii, could provide protection against bacterial pneumonia and serve as next-generation probiotic.
METHODS: We pretreated C57BL/6J mice with butyrate, F. prausnitzii or A. soehngenii, and subsequently infected them intranasally with Klebsiella pneumoniae. To assess the relevance in humans, we assessed associations between rectal levels of Faecalibacterium, immune responses, and clinical outcomes in 115 patients with community-acquired pneumonia (CAP), and in a separate validation cohort.
RESULTS: Pretreatment with F. prausnitzii, but not A. soehngenii, protected mice against bacterial pneumonia, as reflected by reduced bacterial growth and dissemination, lessened organ damage and dampened inflammation. Similar to butyrate pretreatment, F. prausnitzii resulted in reduced pulmonary IL-6 and CXCL-1. In humans, gut Faecalibacterium was decreased during CAP compared to matched controls. CAP patients with higher gut Faecalibacterium levels had lower IL-6-producing capacity and downregulated inflammatory gene expression. Higher intestinal Faecalibacterium levels were associated with better clinical outcomes in independent cohorts of CAP and critically ill patients, which remained significant when controlled for potential confounders.
CONCLUSION: This is the first study showing that the gut commensal Faecalibacterium prausnitzii provides protection against bacterial pneumonia and has translational potential. This motivates future studies investigating the clinical potential of F. prausnitzii as novel probiotic for pneumonia.

DOI: https://doi.org/10.1183/13993003.02208-2024
Trends Immunol. 2025 Aug 07. pii: S1471-4906(25)00180-2. [Epub ahead of print]

Inosine boosts infant antiviral immunity.

Ziad Al Nabhani.

Early antibiotic exposure disrupts the gut microbiota, impairing newborn antiviral immunity. Stevens et al. uncover that inosine, a metabolite produced by gut bacteria, restores the function of antiviral T cells by modulating gene regulation, boosting lung immune defenses against respiratory viruses.

DOI: https://doi.org/10.1016/j.it.2025.07.013
JCI Insight. 2025 Aug 08. pii: e191090. [Epub ahead of print]10(15):

A prometabolite strategy inhibits cardiometabolic disease in an ApoE-/- murine model of atherosclerosis.

Taryn N Beckman, Lisa R Volpatti, Salvador Norton de Matos, Anna J Slezak, Joseph W Reda, Ada Weinstock, Leah Ziolkowski, Alex Turk, Erica Budina, Shijie Cao, Gustavo Borjas, Jung Woo Kwon, Orlando deLeon, Kirsten C Refvik, Abigail L Lauterbach, Suzana Gomes, Eugene B Chang, Jeffrey A Hubbell.

  Butyrate, a microbiome-derived short-chain fatty acid with pleiotropic effects on inflammation and metabolism, has been shown to significantly reduce atherosclerotic lesions, rectify routine metabolic parameters such as low-density lipoprotein cholesterol (LDL-C), and reduce systemic inflammation in murine models of atherosclerosis. However, its foul odor, rapid metabolism in the gut and thus low systemic bioavailability limit its therapeutic effectiveness. Our laboratory has engineered an ester-linked L-serine conjugate to butyrate (SerBut) to mask its taste and odor and to coopt amino acid transporters in the gut to increase its systemic bioavailability, as determined by tissue measurements of free butyrate, produced by hydrolysis of SerBut. In an apolipoprotein E-knockout (ApoE)-/- mouse model of atherosclerosis, SerBut reduced systemic LDL-C, proinflammatory cytokines, and circulating neutrophils. SerBut enhanced inhibition of plaque progression and reduced monocyte accumulation in the aorta compared with sodium butyrate. SerBut suppressed liver injury biomarkers alanine transaminase and aspartate aminotransferase and suppressed steatosis in the liver. SerBut overcomes several barriers to the translation of butyrate and shows superior promise in slowing atherosclerosis and liver injury compared with equidosed sodium butyrate.

Keywords:  Atherosclerosis; Inflammation; Obesity; Therapeutics; Transport

DOI:  https://doi.org/10.1172/jci.insight.191090
Parasit Vectors. 2025 Aug 04. 18(1): 333

Toxoplasma gondii-induced host's high secretion of 25-hydroxycholesterol for immunoprotection.

Zi-Han Yang, Wei-Ling Wu, Jia-Jia Zheng, Chi Zhang, Ying-Ying Lu, Hong-Juan Peng.

   BACKGROUND: Toxoplasma gondii, a parasitic protozoan affecting approximately one-third of global population, causes opportunistic toxoplasmosis. It penetrates barriers to immune-privileged sites, causing encephalitis, retinochoroiditis, and fetal damage. The infection may be linked to neurodegenerative and psychiatric disorders. The T. gondii-host interaction mechanism remains central to understanding its pathogenesis. The changes in small molecule metabolites after infection, which affects the central nervous system (CNS) normal function, have been poorly characterized.
METHODS: The metabolic alterations in brain tissues of sv129 mice infected by T. gondii at 9 days post-infection (DPI) were analyzed through untargeted metabolomic detection. Cholesterol metabolic reprogramming was assessed through analysis of related gene's transcription with quantitative reverse transcription polymerase chain reaction (qRT-PCR). The primary target cells responsible for cholesterol metabolic dysregulation were identified through detection of the secreted cytokines with enzyme-linked immunosorbent assay (ELISA). The T. gondii replication in host cells treated with 25-HC was evaluated using immunofluorescence assay (IFA). Transcriptomic analysis was performed to identify the differentially expressed genes (DEGs) in the host cells infected by T. gondii and/or treated with 25-HC, and the host cell M1 polarization was confirmed by qRT-PCR.
RESULTS: Brain metabolomic profiling identified 19 differentially expressed metabolites (including 25-HC), primarily involved in amino acid metabolism and cholesterol metabolism pathways (biosynthesis of primary bile acids and steroids). Toxoplasma gondii infection triggered host cholesterol metabolic reprogramming and promoted 25-HC secretion from glial cells, which indirectly inhibited T. gondii's proliferation in host cells. Transcriptomic analysis revealed that 25-HC upregulated the expression of chemokines, C-type lectin receptors, and inflammation-related genes. Notably, 25-HC was verified to confer host resistance against T. gondii infection by promoting microglial M1 polarization.
CONCLUSIONS: Our study demonstrated that T. gondii infection activates the CH25H-25-HC axis to induce microglial M1 polarization and cytokine secretion, thereby establishing an anti-Toxoplasma defense. These findings highlight the central role of cholesterol metabolism in T. gondii pathogenesis and provide innovative strategies for the diagnosis, prevention, and treatment of toxoplasmosis.

Keywords:  25-hydroxycholesterol; Cholesterol metabolism; Metabolomics; Microglia; Toxoplasma gondii; Transcriptomics

DOI:  https://doi.org/10.1186/s13071-025-06890-0