bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2025–06–01
twenty-two papers selected by
Dylan Ryan, University of Cambridge



  1. Chin Med J (Engl). 2025 May 29.
       BACKGROUND: Macrophage polarization anomalies and dysfunction play a crucial role in the pathogenesis of immune thrombocytopenia (ITP). Itaconate is a Krebs cycle-derived immunometabolite synthesized by myeloid cells to modulate cellular metabolism and inflammatory responses. This study aimed to evaluate the immunoregulatory effects of an itaconate derivative on macrophages in patients with ITP.
    METHODS: Peripheral blood-derived macrophages from patients with ITP and healthy controls were treated with 4-octyl itaconate (4-OI), a derivative of itaconate that can penetrate the cell membrane. Macrophage polarization, antigen-presenting functions, and phagocytic capability were measured via flow cytometry and enzyme-linked immunosorbent assay (ELISA). Macrophage glycolysis in patients with ITP and the metabolic regulatory effect of 4-OI were detected using a Seahorse XFe96 Analyzer. An active murine model of ITP was used to evaluate the therapeutic effects of 4-OI in vivo.
    RESULTS: 4-OI reduced the levels of CD80 and CD86 in M1 macrophages and suppressed the release of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 pro-inflammatory cytokines, suggesting that 4-OI could hinder the polarization of macrophages toward an M1 phenotype. We found that 4-OI pretreated M1 macrophages reduced the proliferation of CD4+ T cells and promoted the differentiation of regulatory T cells. In addition, after 4-OI treatment, the phagocytic capacity of M1 macrophages toward antibody-coated platelets decreased significantly in patients with ITP. In addition, the glycolytic function of M1 macrophages was elevated in individuals with ITP compared to those in healthy controls. 4-OI treatment downregulated glycolysis in M1 macrophages. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) also inhibited the polarization of M1 macrophages and restored their functions. In vivo, 4-OI treatment significantly increased platelet counts in the active ITP murine model.
    CONCLUSIONS: Itaconate derivative 4-OI inhibited M1 macrophage polarization and restored impaired functions through metabolic reprogramming. This study provides a novel therapeutic option for ITP.
    Keywords:  4-Octyl itaconate; Glycolysis; Immune thrombocytopenia; Macrophages
    DOI:  https://doi.org/10.1097/CM9.0000000000003586
  2. Endocr J. 2025 May 27.
      Immune cells undergo substantial metabolic rewiring during differentiation and activation to satisfy the energy demands of an appropriate immune response. Lipids serve as energy sources and function as essential components of cellular membranes and signaling molecules. Recent studies have revealed that reprogramming of lipid metabolism, including lipid uptake, de novo synthesis of cholesterol and fatty acids, and fatty acid oxidation, leads to dynamic alterations in the quantity and quality of intracellular lipids. These metabolic changes play crucial roles in shaping immune cell functions, promoting anti-inflammatory responses, and facilitating the resolution of inflammation. Conversely, dysregulation of lipid metabolism can result in immune cell dysfunction, contributing to the onset and progression of chronic inflammatory diseases such as autoimmune diseases and metabolic syndrome. Notably, cholesterol and fatty acid metabolism influence immune responses by modulating membrane lipid composition and downstream inflammatory signaling. Given these insights, targeting lipid metabolism has emerged as a promising therapeutic approach for restoring immune homeostasis and treating chronic inflammatory diseases.
    Keywords:  Autoimmunity; Chronic inflammation; Immune responses; Immunometabolism; Lipid metabolism
    DOI:  https://doi.org/10.1507/endocrj.EJ25-0180
  3. Cell Mol Life Sci. 2025 May 28. 82(1): 218
      The integration of metabolic programs with T cell signaling establishes a molecular foundation for immune metabolism. As a key metabolic regulator, GSK3β's activity is dynamically modulated by phosphorylation at Ser9 and Tyr216. However, the contribution of these phosphorylation sites on metabolism-driven T cell response remains unclear. Using tilapia and mouse models, we investigated the regulation of GSK3β on T cell metabolism and its evolutionary variation. In tilapia, T cell activation induces GSK3β signaling, linking to both glycolysis and oxidative phosphorylation (OXPHOS). Tyr216 phosphorylation preferentially promotes glycolysis, facilitating T cell activation, proliferation, and antibacterial immunity; while inhibition of Ser9 phosphorylation specifically enhances OXPHOS to sustain T cell responses. Differently, Tyr216 phosphorylation supports both glycolysis and OXPHOS in mouse, ensuring CD4+ T and CD8+ T cell activation, proliferation, and cytokine production. Although Ser9 phosphorylation controls OXPHOS, its inhibition impairs rather than enhances OXPHOS and CD4+ T cell responses in mouse. We thus revealed a previously unknown mechanism underlying T cell metabolism and proposed that, through evolution, GSK3β has restructured the regulatory strategy, enabling bidirectional control of T cell metabolism and immunity in mammals and enhancing the flexibility of the adaptive immune system.
    Keywords:  Evolution; Fish; GSK3β; Immunometabolism; T cells
    DOI:  https://doi.org/10.1007/s00018-025-05746-1
  4. Pharmacol Res. 2025 May 27. pii: S1043-6618(25)00228-2. [Epub ahead of print]217 107803
      Immunometabolism has received significant interest as a field exploring the dynamic interation between the immune system and metabolic processes. Immune cell activation, proliferation, and function are tightly regulated by metabolism, and metabolic products influence immune responses. These two aspects interact to maintain internal homeostasis. Disruption of immunometabolism plays a crucial role in the onset and progression of autoimmune diseases. Metabolic abnormalities may cause abnormal activation and differentiation of immune cells, leading to attacks on self-tissues. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by platelet dysfunction and impaired production, which are closely related to metabolic dysfunction. Alterations in glycolysis, fatty acid oxidation, and amino acid metabolism affect platelet function and immune cell behavior, contributing to disease progression. This review discusses the role of immunometabolism in ITP, highlights recent advances in diagnosis and treatment, and explores potential therapeutic strategies.
    Keywords:  Glycolysis; ITP; Immunometabolism; Metabolic Reprogramming
    DOI:  https://doi.org/10.1016/j.phrs.2025.107803
  5. Front Immunol. 2025 ;16 1573039
      The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.
    Keywords:  cancer therapy; immune regulation; lactate metabolism; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1573039
  6. Metabolites. 2025 Apr 22. pii: 285. [Epub ahead of print]15(5):
      Background/Objectives: HIV and Mycobacterium tuberculosis (M.tb) co-infection presents a major global health burden. The immune response to M.tb is largely orchestrated by cluster of differentiation 4-positive (CD4+) T cells, with CD8+ T cells playing an auxiliary role. This study aims to investigate the immunometabolic response of CD4+ and CD8+ T cells to M.tb antigens, analysed using metabolomics, to elucidate metabolic shifts that may influence immune function in an HIV+ environment. Methods: Whole blood samples from newly diagnosed, treatment-naïve HIV+ individuals were stimulated with M.tb antigens early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) using the QuantiFERON® (QFT) Gold Plus assay. Following incubation, plasma samples were analysed through untargeted nuclear magnetic resonance (1H-NMR) spectroscopy. Metabolomic data were processed using MetaboAnalyst, with differential metabolites identified through multivariate statistical analyses. Results: Metabolic profiling of PBMCs revealed distinct differences in response to M.tb antigens between CD4+ and CD4+/CD8+ T-cell activation. CD4+ T cells exhibited enhanced glycolysis, with elevated levels of metabolites that are linked largely to the Warburg effect. Additionally, vitamin D levels were found to correlate with certain metabolites, suggesting a role in modulating immune responses. Conclusions: These findings suggest a complex interplay between immune cell metabolism and activation in HIV+ individuals. The study demonstrates that HIV and M.tb co-infection significantly influences the broader metabolic profile of peripheral blood mononuclear cells (PBMCs), highlighting the altered metabolic pathways that are critical in immune responses and disease progression. These findings contribute to the understanding of immunometabolism in co-infection and emphasise the need for further research into targeted metabolic interventions.
    Keywords:  CD4+ T cells; HIV; Mycobacterium tuberculosis; immunometabolism; metabolic pathways; metabolomics
    DOI:  https://doi.org/10.3390/metabo15050285
  7. Immunology. 2025 May 27.
      Non-catalytic region of tyrosine kinase 1 (Nck1) is an adaptor protein found in many cell types and plays several functions. In T cells, Nck1 is functionally associated with a T cell receptor (TCR)-mediated actin rearrangement, insulin signalling, PI3K/Akt/mTOR pathway, and lipid production. However, the role of Nck1 in regulating glucose metabolism in T cells is still largely unknown. In the present study, the role of Nck1 in glucose metabolism in primary human T cells was investigated. Plasmid encoding Nck1-specific short hairpin RNA (shRNA) was delivered to primary T cells to mediate Nck1 silencing. Plasmids encoding Nck1-specific short hairpin RNA (shRNA) were delivered to primary human T cells to mediate Nck1 silencing. Nck1-knockdown (N1KD) cells were analysed for processes related to glucose metabolism and function. Despite an increased expression of glucose transporter 1 (GLUT1) in N1KD cells, these cells exhibited impaired glucose uptake and ATP production, indicating dysfunction of GLUT1 or altered intracellular glucose metabolism. Nck1 depletion disrupted metabolic signalling characterised by reduced TXNIP and phosphoribosomal protein S6 (pS6) levels, along with an increased phosphorylation of Akt and AMPK. The reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) found in N1KD cells indicated impaired glycolysis and oxidative phosphorylation. Functionally, these metabolic alterations were associated with impaired T cell activation, reduced proliferation, and increased apoptosis. Collectively, Nck1 critically regulated glucose metabolism in T cells, linking metabolic reprogramming to immune function and cell survival.
    Keywords:  Nck1; T cell; T cell activation; T cell signalling; glucose metabolism
    DOI:  https://doi.org/10.1111/imm.13950
  8. Am J Respir Cell Mol Biol. 2025 May 29.
      Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) have elevated ANT1 compared to normal control subjects. Ant1-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. Ant1-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional Ant1 knockout in Cx3cr1-positive monocytes and adoptive transfer of Ant1-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD.
    Keywords:  copd; emphysema; macrophage migration; metabolism; mitochondria
    DOI:  https://doi.org/10.1165/rcmb.2024-0469OC
  9. Cell Mol Immunol. 2025 May 26.
      Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.
    Keywords:  CD39 antisense; Immune metabolism; Inflammatory bowel disease; Th17 cell; Treg
    DOI:  https://doi.org/10.1038/s41423-025-01295-6
  10. Nature. 2025 May 28.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01621-y
  11. Curr Opin Immunol. 2025 May 26. pii: S0952-7915(25)00042-1. [Epub ahead of print]95 102566
      Mitochondrial diseases (MtD) provide a unique window into the complex interplay between metabolism and immune function. These rare disorders, caused by defects in oxidative phosphorylation, result in bioenergetic deficiencies that disrupt multiple organ systems. While traditionally studied for their metabolic impact, MtD also profoundly affect the immune system, altering both innate and adaptive responses. This review explores how mitochondrial dysfunction shapes immune dysregulation, influencing thymocyte maturation, regulatory T cells, and B cell function while also driving innate immune activation through mitochondrial DNA instability and type I interferon signaling. Additionally, MtD highlight an emerging overlap between inborn errors of metabolism and inborn errors of immunity, revealing shared pathways that connect mitochondrial dysfunction to immune deficiencies and inflammatory disease. Studying MtD not only advances our understanding of immunometabolism but also provides critical insights into more common inflammatory and autoimmune conditions, offering potential therapeutic targets that extend beyond rare mitochondrial disorders.
    DOI:  https://doi.org/10.1016/j.coi.2025.102566
  12. Am J Physiol Gastrointest Liver Physiol. 2025 May 26.
      Inflammatory bowel diseases (IBD) and gut barrier impairment are associated with changes in dietary tryptophan and arginine metabolism, but mechanisms of barrier perturbation and restoration are unclear. We show here that the widely consumed probiotic Lacticaseibacillus rhamnosus GG (LGG) enhances gut barrier functions in part through stimulating the intestinal arginine metabolic pathway, and this mechanism depends on the sufficiency of dietary tryptophan in the host. Specifically, LGG markedly upregulates argininosuccinate lyase (ASL), the enzyme that breaks down argininosuccinate into arginine. ASL expression is markedly reduced during experimental colitis with an accumulation of serum argininosuccinate. LGG colonization in mice reduces serum argininosuccinate, a metabolite that inversely correlates with tight junction gene expression, impairs barrier function and exacerbates DSS colitis. We show that LGG-derived indoles as well as arginine metabolites enhanced Asl and Nos2 expression, linking microbial metabolism to nitric oxide production and epithelial homeostasis. IBD patients have increased ASS1 and decreased ASL expression, suggesting a metabolic bottleneck driving ASA accumulation. We propose that signaling pathways underlying LGG and tryptophan mediated ASL upregulation can be useful therapeutic targets to normalize arginine metabolism in select IBD patients.
    Keywords:  Inflammatory bowel disease; Intestine; Probiotics; Tight Junction; Tryptophan
    DOI:  https://doi.org/10.1152/ajpgi.00366.2024
  13. Sci Rep. 2025 May 28. 15(1): 18741
      Metabolic reprogramming within the tumor microenvironment (TME) plays a central role in cancer progression and immune evasion, with L-arginine metabolism emerging as a key regulatory axis. Arginase overexpression depletes intratumoral L-arginine, thus suppressing T-cell proliferation while fuelling tumor growth through polyamine biosynthesis. OATD-02, a novel dual arginase (ARG1/ARG2) inhibitor, reprograms tumor metabolism by restoring L-arginine availability and reducing the levels of polyamines, thereby shifting the TME toward a more immunostimulatory state. Unlike ARG1-selective inhibitors with limited intracellular uptake, OATD-02 effectively inhibits both extracellular and intracellular arginases, thereby addressing a major limitation of first-generation arginase inhibitors. To visualize the pharmacodynamic effects of OATD-02 dosing in mice with spatial resolution, we employed MALDI mass spectrometry imaging (MALDI-MSI), thus enabling direct mapping of metabolic changes within tumor tissues. In preclinical models, OATD-02 treatment led to widespread accumulation of intratumoral L-arginine with concomitant depletion of polyamines and resulted in metabolic shifts that correlated with increased immune cell infiltration and an improved response to immune checkpoint blockade. These findings underscore the role of dual arginase inhibition in reshaping tumor metabolism and overcoming immune suppression by restoring the metabolic fitness of immune cells to fight cancer. The metabolic changes caused by OATD-02 treatment resulted in significantly enhanced antitumor immune responses, increased T-cell infiltration in tumors, expansion of CD8⁺ T cells in draining lymph nodes, and systemic upregulation of T-cell activation markers. These effects translated into a substantial survival benefit in the CT26 tumor model, particularly when combined with anti-PD-1 therapy, where OATD-02 improved checkpoint blockade efficacy by relieving metabolic constraints affecting tumor-infiltrating lymphocytes. By leveraging the unique capabilities of MALDI-MSI, this study provides high-resolution metabolic insights into the mechanism of action of OATD-02, reinforcing its potential as a next-generation metabolic-immunotherapeutic agent. The observed metabolic reprogramming, coupled with enhanced immune activation and prolonged survival, supports the clinical development of OATD-02 as a promising strategy for enhancing cancer immunotherapy efficacy. OATD-02 is currently undergoing clinical evaluation in a phase I/II trial (NCT05759923), which will further elucidate its safety and therapeutic impact. These findings highlight the potential of arginase-targeted therapies in cancer treatment and underscore the value of MALDI-MSI as a powerful tool for tracking metabolic responses to therapy.
    Keywords:  Anticancer therapy; Arginine metabolism; Dual arginase Inhibition; Immune modulation; MALDI imaging; Metabolic reprogramming; Mitochondrial metabolism; OATD-02; Polyamines; Tumor metabolism
    DOI:  https://doi.org/10.1038/s41598-025-03446-1
  14. Front Oncol. 2025 ;15 1553284
      Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy, characterized by metabolic reprogramming. This reprogramming creates an acidic and hypoxic environment within tumor cells to adapt to metabolic changes. Experimental data indicate that in HNSCC, the metabolic reprogramming of tumor cells regulates immune cells via metabolites or signaling pathways, thereby promoting cancer progression or immune evasion. This article reviews the metabolic reprogramming in HNSCC, including glucose, fatty acids, amino acids, and nucleotide metabolism. These metabolic pathways play crucial roles in the proliferation, differentiation, and effector functions of immune cells, and influence immunosuppressive checkpoints. Additionally, this review explores the potential relationships between metabolic reprogramming, tumor immunity, and related treatments. Thus, targeting metabolic reprogramming and interactions between immune cells may help overcome therapeutic resistance in HNSCC patients.
    Keywords:  HNSCC; immune; metabolic reprogramming; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1553284
  15. Mol Med. 2025 May 29. 31(1): 211
       BACKGROUND: Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.
    METHODS: In this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic-killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.
    RESULTS: Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.
    CONCLUSIONS: We identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic-immune checkpoint and highlight its druggable vulnerability in osteomyelitis.
    Keywords:   S. aureus ; Bactericidal function; MEK1-CHEK2; Macrophage mitophagy; Osteomyelitis
    DOI:  https://doi.org/10.1186/s10020-025-01274-7
  16. Microb Pathog. 2025 May 27. pii: S0882-4010(25)00482-6. [Epub ahead of print]206 107757
       BACKGROUND: The pathogenic mechanism of mycobacterium tuberculosis (Mtb) is complex, and the immune mechanism of the host against Mtb infection and the escape mechanism of Mtb are not fully understood. This study aimed to explore the mechanisms underlying complement C1q and Mtb immune escape.
    METHODS: Functional experiments, using RAW264.7 cells as the focus cell line and applying CCK-8, western blotting, qRT-PCR, and flow cytometry, were carried out to uncover the exact role of C1q in macrophages, glycolytic activation, immune escape, and Mtb.
    RESULTS: C1q promoted the proliferation of RAW264.7, suppressed cell apoptosis, and regulated the secretion of M1/M2 type molecular markers in RAW264.7 cells. Moreover, C1q induced glycolytic activation in macrophages, and the immune escape of Mtb in the macrophages was accompanied by the activation of glycolysis.
    CONCLUSION: Complement C1q inhibited the immune escape of Mtb associated with macrophage inflammation and glycolytic activation.
    Keywords:  C1q; Glycolytic activation; Immune escape; Macrophage; Mycobacterium tuberculosis
    DOI:  https://doi.org/10.1016/j.micpath.2025.107757
  17. Med Microbiol Immunol. 2025 May 28. 214(1): 26
      Airway epithelial cells play a pivotal role in the early host response to Mycoplasma pneumoniae colonization. Our previous study has revealed that M. pneumoniae infection induces metabolic reprogramming in bronchial epithelial cells. However, the mechanisms underlying these metabolic shifts and their contribution to the pathogenesis of pneumonia remain unclear. Herein, we demonstrate that M. pneumoniae infection activates signal transducer and activator of transcription 3 (STAT3), which drives citrate accumulation in airway epithelial cells. Citrate is metabolized by adenosine triphosphate-citrate lyase (ACLY) into acetyl coenzyme A, which is further converted to malonyl coenzyme A, promoting post-translational modifications such as histone acetylation and glyceraldehyde-3-phosphate dehydrogenase malonylation (GAPDH). In vivo, pharmacological inhibition of STAT3 or ACLY attenuated pulmonary inflammation and pro-inflammatory cytokine expression yet paradoxically delayed pathogen clearance, as evidenced by increased colonyforming units in bronchoalveolar lavage fluid and lung tissue. These findings demonstrate that targeting the STAT3/ACLY axis exerts antiinflammatory potential without direct antibacterial activity. Our work highlights the dual regulatory roles of citrate metabolism in inflammation and pathogen control and suggests that combined use of STAT3/ACLY inhibitors with conventional antibiotics may be necessary to achieve both immunomodulation and effective bacterial eradication.
    Keywords:   Mycoplasma pneumoniae ; ATP-citrate lyase; Airway epithelial cells; Citrate; STAT3
    DOI:  https://doi.org/10.1007/s00430-025-00836-0
  18. Acta Pharmacol Sin. 2025 May 27.
      Glucose metabolism disorder is an important hallmark of rheumatoid arthritis (RA). Inhibiting key glycolysis enzymes is the primary approach, but effective treatments targeting glycolytic metabolism have not yet reached clinical practice. G protein-coupled receptor kinase 2 (GRK2) as a multi-signals regulatory hub has attracted wide attention. In this study, we investigated the role of GRK2 inhibitor on glycolysis of monocyte-derived macrophages (MDMs), the primary source of inflammatory mediators in RA synovium. Human peripheral mononuclear cells were obtained from RA patients and differentiated into MDMs with M-CSF (100 ng/ml) for 5 days. By analyzing the metabolic status of RA MDMs in normoxia and hypoxia, we found that glycolysis was increased in RA MDMs, and inhibiting glycolysis could suppress the macrophage inflammatory phenotype. The antiglycolytic role of GRK2 deletion was tested in MDMs in vitro and in vivo. We conducted proteomics and mass spectrometric analysis and confirmed the inhibitory role of GRK2 on several key glycolytic enzymes. GRK2 maintained PKM2 tetramer stability through two synergistic modifications-phosphorylation at S406 and de-succinylation at K433. In RA, decreased cytoplasmic GRK2 protein levels impaired its regulation toward PKM2, leading to enhanced glycolysis and accelerating RA progression. Administration of GRK2 inhibitors paroxetine, CP-25, or the glycolysis inhibitor 2-DG for 21 days in the CIA mouse model all restored cytoplasmic GRK2 levels and homeostatic regulation, offering a potential therapeutic approach for RA glycolysis.
    Keywords:  GRK2; PKM2; glycolysis; rheumatoid arthritis; synovial macrophages
    DOI:  https://doi.org/10.1038/s41401-025-01582-y
  19. Cell Rep. 2025 May 28. pii: S2211-1247(25)00536-4. [Epub ahead of print]44(6): 115765
      An animal's metabolic state strongly influences its behavior. Hungry animals prioritize food-seeking and feeding behaviors, while sated animals suppress these behaviors to engage in other activities. Additionally, neuronal activity and synaptic transmission are among the most energy-expensive processes. However, neurons do not uptake nutrients from the circulation. Instead, glia fulfill this highly evolutionarily conserved function in addition to modulating neuronal activity and behavior. However, how different glia subtypes sense metabolic state and modulate behavior is incompletely understood. Here, we unravel two types of glia-mediated modulation of metabolic-state-dependent behavior. In food-deprived flies, astrocyte-like and perineurial glia promote foraging and feeding, respectively, while cortex glia suppress these behaviors. We further show that adenosine and adenosine receptors modulate intracellular calcium levels in these glia subtypes, which ultimately controls behavior. This study reveals a mechanism of how different glia subtypes sense an animal's metabolic state and modulate its behavior accordingly.
    Keywords:  CP: Metabolism; Drosophila; adenosine; chemosensation; feeding; glia; metabolic-state-dependent behavior; metabolism; neural circuits
    DOI:  https://doi.org/10.1016/j.celrep.2025.115765
  20. J Leukoc Biol. 2025 May 28. pii: qiaf077. [Epub ahead of print]
      Transcription factors TFEB and TFE3 are crucial for regulating autophagy, lysosomal biogenesis, and lipid metabolism, and have significant roles in macrophage function and innate immunity. The alpha7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated Ca2+ channel known for its therapeutic potential in neurological and inflammatory disorders, has been implicated in modulating immune responses by modulating macrophage function. Stimulation of α7nAChR with chemical agonists has been claimed to activate TFEB in pancreatic acinar cells and neurons. However, the impact of α7nAChR activation on TFEB and TFE3 in macrophages remained unknown, posing an important question due to the potential implications for inflammation regulation. This study investigates the effects of acute α7nAChR activation on TFEB-mediated responses in murine macrophages using the specific agonist PNU-282987. We demonstrate that α7nAChR stimulation triggers TFEB nuclear translocation and lysosomal expansion. Surprisingly, PNU-282987 induces a broad pro-inflammatory gene signature without concomitant cytokine secretion, suggesting an uncoupling of gene expression from cytokine release. Mechanistically, TFEB activation requires the lysosomal Ca2+ exporter MCOLN1 and the Ca2+-dependent phosphatase PPP3/calcineurin. Additionally, PNU-282987 elevates reactive oxygen species (ROS) levels, and ROS are involved in TFEB activation by PNU-282987. Notably, even with α7nAChR deletion, compensatory ROS-mediated TFEB activation persists, suggesting the involvement of additional mechanisms of action for PNU-282987. Our findings reveal a novel α7nAChR-TFEB signaling axis in macrophages, offer new insights into the cholinergic regulation of immune responses, establish a baseline for comparison with disease states, and identify potential therapeutic targets for modulating inflammation.
    Keywords:  Inflammation and immune regulation; Lysosomes; Macrophages; TFEB; α7 nicotinic acetylcholine receptor (α7nAChR)
    DOI:  https://doi.org/10.1093/jleuko/qiaf077
  21. Int J Mol Sci. 2025 May 09. pii: 4527. [Epub ahead of print]26(10):
      Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are autoimmune diseases associated with chronic inflammation and cardiovascular risk. This study aimed to identify metabolic alterations in Colombian women with RA and SLE to discover potential biomarkers. Plasma samples were analyzed using LC-QTOF-MS and GC-QTOF-MS. Correlation network analysis assessed relationships between metabolites, cytokines, and HDL levels. A generalized linear model (GLM) combined metabolite scores, and ROC analysis evaluated their predictive performance. Significant metabolic changes were observed, including decreased phospholipids and sphingolipids, and increased glycerolipids in RA and SLE compared to healthy controls. The metabolite-cytokine network revealed correlations between FA 18:0 and DG 37:7 with cytokines, linking lipid metabolism to inflammation. PS O-40:3 and FA 18:0 in RA and PC O-28:0 and DG 37:7 in SLE distinguished patients from healthy controls. The combination of PS O-40:3 and FA 18:0 in RA (AUC = 0.997) and PC O-28:0 and DG 37:7 in SLE (AUC = 0.949) demonstrated high predictive performance. PE O-42:5 was positively correlated with HDL, suggesting a potential protective role against cardiovascular disease. These findings highlight lipid metabolism's role in RA and SLE and support specific metabolites as biomarkers for disease differentiation, inflammation, and cardiovascular risk. These insights could lead to improved diagnostics and targeted treatments for these autoimmune diseases.
    Keywords:  HDL; cytokines; metabolites; rheumatoid arthritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.3390/ijms26104527
  22. Int J Mol Sci. 2025 May 21. pii: 4946. [Epub ahead of print]26(10):
      Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.
    Keywords:  T cell activation; T cell metabolism; Th17 lymphocytes; Wnt/β-catenin signaling pathway; domestic dog model; interleukin-17; magnetic EpoxyBeads; memory phenotype
    DOI:  https://doi.org/10.3390/ijms26104946