Immunometabolism (Cobham (Surrey, England))最新文献

{"title":"Meta-inflammation through the lens of macrophage programming and nutrient-sensing ghrelin signaling.","authors":"Hye Won Han, Da Mi Kim, Sahar Eshghjoo, Chenxi Xu, Zeyu Liu, Bhimanagouda S Patil, Shaodong Guo, Yuxiang Sun","doi":"10.1097/IN9.0000000000000088","DOIUrl":"10.1097/IN9.0000000000000088","url":null,"abstract":"<p><p>Macrophages are at the critical interface of immunity and metabolism. Metabolic reprogramming of macrophages, also known as meta-inflammation, has major implications in the pathogenesis of many chronic diseases. The infiltration and polarization of macrophages play critical roles in tissue homeostasis and inflammatory responses, thereby reshaping the tissue microenvironment. Macrophages have unique phenotypical and functional plasticity, making them attractive as therapeutic targets. Nutrient-sensing ghrelin is a gastrointestinal peptide hormone that functions through its receptor, growth hormone secretagogue receptor (GHSR), and is known to trigger hunger sensation, stimulate food intake, and promote fat deposition. Emerging evidence indicates that ghrelin/GHSR signaling is also a critical regulator of immunometabolism, modulating metabolic pathways in macrophages to enable their adaptation and functional responses to the tissue microenvironment. Here, we highlight the regulatory mechanisms of the ghrelin/GHSR system in macrophage reprogramming in meta-inflammation. In particular, we demonstrate the infiltration and differentiation of tissue-resident macrophages, and their functional impacts on the development and progression of metabolic and inflammatory dysfunctions. The dynamic and multifaceted roles of ghrelin/GHSR signaling in macrophage reprogramming could be leveraged to develop novel immunotherapies for meta-inflammatory conditions and diseases.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 3","pages":"e00088"},"PeriodicalIF":3.9,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial reactive oxygen species regulate HIF-1α stabilization and methylglyoxal accumulation in classically activated mouse macrophages.","authors":"Daniel Prantner, Mark A Watson, Martin D Brand, Jules C Paton, Stefanie N Vogel","doi":"10.1097/IN9.0000000000000085","DOIUrl":"10.1097/IN9.0000000000000085","url":null,"abstract":"<p><strong>Background: </strong>The economic and medical burden of sepsis worldwide underscores the need for novel therapeutics. Early sepsis involves dramatic metabolic changes. Classically activated macrophages, stimulated with lipopolysaccharide and interferon-γ, shift their metabolism to glycolysis. The reactive glycolytic metabolite, methylglyoxal, accumulates and has been associated with adverse outcomes in sepsis. We previously demonstrated that hypoxia-inducing factor-1α (HIF-1α) contributes to methylglyoxal accumulation. Treatment with lipopolysaccharide or interferon-γ individually stabilized HIF-1α protein; however, co-stimulation with both lipopolysaccharide and interferon-γ accelerated HIF-1α stabilization, implying a shared upstream mediator. Therefore, we sought to characterize mechanisms underlying methylglyoxal accumulation.</p><p><strong>Methods: </strong>Quantitative polymerase chain reaction and immunoblotting were used to analyze HIF-1α expression in classically activated primary mouse macrophages.</p><p><strong>Results: </strong><i>Nos2</i> expression was induced by lipopolysaccharide or interferon-γ and markedly enhanced by combined treatment, possibly linking inducible nitric oxide synthase (iNOS) activity to HIF-1α stabilization. Inhibiting iNOS with l-NG-Nitro arginine methyl ester (l-NAME) reduced HIF-1α stabilization in a dose-dependent manner. Mitochondrial reactive oxygen species (mROS), generated following nitric oxide inhibition of cytochrome oxidase, similarly contributed to HIF-1α stabilization, as shown by the effects of suppressors of ROS production by mitochondrial complex I (S1QEL1.1) and III (S3QEL1.2) and the compartment-specific antioxidant Mito-TEMPO. Blocking mROS also decreased <i>Il1b, Il6, and Cxcl10</i> expression in activated macrophages, supporting a broader impact on inflammation. Additionally, S1QEL1.1 treatment reduced accumulation of methylglyoxal.</p><p><strong>Conclusions: </strong>These data support a model in which nitric oxide-mediated mitochondrial dysfunction increases mROS, promoting HIF-1α stabilization and methylglyoxal accumulation, thereby shaping macrophage inflammatory responses. Thus, targeting mROS may offer a therapeutic strategy to improve sepsis outcomes.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 3","pages":"e00085"},"PeriodicalIF":3.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-specific roles of monoacylglycerol (MAG) in metabolic diseases.","authors":"Min Young Park, Ashley Mooring, Joanne Bruno, José O Alemán","doi":"10.1097/IN9.0000000000000087","DOIUrl":"10.1097/IN9.0000000000000087","url":null,"abstract":"<p><p>Monoacylglycerol (MAG) is an important bioactive lipid metabolite/intermediate, playing crucial roles in energy homeostasis and cellular signaling. This review explores MAG's chemical structure, classification, and metabolic pathways. We also discuss the emerging evidence for MAG as a signaling molecule, with particular emphasis on their interactions with cannabinoid receptor 1 and cannabinoid receptor 2 and G-protein-coupled receptor 119. We focus on examining the diverse and tissue-specific functions of MAG in the context of metabolic diseases, including the roles of MAG in nutrient absorption, appetite regulation, obesity, glucose homeostasis, and lipid metabolism. Furthermore, we address therapeutic approaches in modulating MAG metabolism and challenges in development, considering the complexity of targeting peripheral tissues. This review provides insights into the multifaceted roles of MAG in metabolic health and disease, paving the way for novel therapeutic strategies in the management of metabolic disorders.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 3","pages":"e00087"},"PeriodicalIF":3.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8⁺ T-cell dysfunction in cancer.","authors":"Desh Raj, Mahesh Kathania, Tuoqi Wu, Arianne L Theiss, K Venuprasad","doi":"10.1097/IN9.0000000000000086","DOIUrl":"10.1097/IN9.0000000000000086","url":null,"abstract":"<p><p>In a recent study published in <i>Science Immunology</i>, Tiberti and colleagues demonstrate that palmitate, a saturated fatty acid enriched in tumors, directly impairs CD8⁺ cytotoxic T lymphocyte function through mitochondrial and epigenetic reprogramming. Palmitate exposure reduced mitochondrial fitness, oxidative phosphorylation, and adenosine triphosphate production, resulting in defective proliferation, cytokine production, and antitumor activity. Mechanistically, mitochondrial dysfunction decreased intracellular acetyl-CoA availability, leading to reduced histone acetylation and loss of chromatin accessibility at loci that control effector programs. The study further identifies sphingosine kinase 2 as a critical mediator of lipid-induced dysfunction. Importantly, SPHK2 inhibition restored mitochondrial function, histone acetylation, and cytotoxic T lymphocyte antitumor activity, highlighting a potential therapeutic strategy for enhancing cancer immunotherapy.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 3","pages":"e00086"},"PeriodicalIF":3.9,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A loss of the cytosolic branched-chain aminotransferase, BCATc, enhances T_h1 differentiation and skews Tregs to acquire a T_h1-like phenotype.","authors":"Tanner J Wetzel, Christie M Adam, Tanner J Kelm, Anna E Kotula, Madison E Fagan, Taha Z Khan, Anthony X Diehl, Melissa A Meyer, Jessica P Sanchez, Brian H Ladle, Elitsa A Ananieva","doi":"10.1097/IN9.0000000000000084","DOIUrl":"10.1097/IN9.0000000000000084","url":null,"abstract":"<p><strong>Background: </strong>T-cell fate and function are profoundly shaped by microenvironmental nutrient availability. The branched-chain amino acid, leucine, is essential for T-cell function, with its uptake via the solute carrier family 7-member 5 transporter increasing upon activation. As the enzyme catalyzing the first step of leucine degradation, the cytosolic branched-chain aminotransferase (BCATc) is induced upon T-cell activation and subsequently acts as a negative regulator of T-cell activity. However, a major knowledge gap remains regarding how BCATc modulates T-cell function beyond activation, specifically within differentiated T helper cells.</p><p><strong>Methods: </strong>Novel T-cell conditional knockout mouse models of BCATc, and its mitochondrial isoenzyme, BCATm, were characterized and used as a source of in vitro or ovalbumin-induced CD4⁺ T-cell subsets in the presence of the leucine competitive antagonist, <i>N</i>-acetyl leucine amide (NALA). The studies were complemented by transcriptomic analysis of human T cells using the genomic platform R2.</p><p><strong>Results: </strong>Loss of BCATc enhanced T_H1 phenotype as evidenced by the increased expression of T-bet and interferon-<i>γ</i>. Leucine, but not the BCAT isoenzymes, was critical for T_H2 and T_H17 function as evidenced by the severe reduction in interleukin [IL]-13 and IL-17 release in the presence of NALA. Lastly, a loss of BCATc, or its mitochondrial isozyme, BCATm, facilitated a shift of regulatory T cells (Tregs) to a T_H1-like phenotype as judged by the increased populations of T-bet⁺Foxp3⁺Tregs.</p><p><strong>Conclusions: </strong>BCATc is the dominant BCAT isoenzyme with immunoregulatory function in CD4⁺ T-cell subsets and targetable potential in T-cell immunity.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 3","pages":"e00084"},"PeriodicalIF":3.9,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13361958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148439258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming the diseased liver: antioxidant-engineered mRNA nanoparticles as microenvironment modulators in MAFLD.","authors":"Matteo Ghiringhelli, Lior Zangi","doi":"10.1097/IN9.0000000000000083","DOIUrl":"10.1097/IN9.0000000000000083","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) is a leading cause of hepatocellular carcinoma (HCC), driven in part by oxidative stress-induced immune dysfunction that limits the efficacy of immunotherapy. In a recent study, Yu et al developed a vitamin E-incorporated lipid nanoparticle designed to enhance hepatocyte‑specific mRNA delivery while simultaneously buffering oxidative stress in the hepatic microenvironment. By restoring the activity of the redox‑sensitive phosphatase T‑cell protein tyrosine phosphatase and suppressing signal transducer and activator of transcription (STAT) signaling, this strategy improves metabolic homeostasis, reduces inflammatory signaling, and enhances responsiveness to immune checkpoint blockade. These findings illustrate how rational nanoparticle engineering can integrate therapeutic delivery with microenvironmental reprogramming in chronic metabolic disease.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 2","pages":"e00083"},"PeriodicalIF":3.9,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147984740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenteric adipose tissue: from protective gatekeeper to driver of inflammatory bowel disease.","authors":"Christy M Gliniak","doi":"10.1097/in9.0000000000000081","DOIUrl":"10.1097/in9.0000000000000081","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) defines a group of diseases, including Crohn's disease and ulcerative colitis, characterized by chronic inflammation of the gastrointestinal tract. Evidence suggests that visceral adipose tissue, particularly its mesenteric component, influences the course of IBD through its immunomodulatory properties. Mesenteric adipose tissue (MAT) is composed of multiple cell types, including adipocytes, preadipocytes, and immune cells, that collectively regulate energy balance and endocrine signaling. MAT is a unique fat depot as it directly connects along most of the intestinal serosa and harbors the arteries, veins, and lymph nodes that support intestinal function. MAT's placement at the intestinal barrier serves to contain microbial translocation and support the repair of intestinal epithelium. However, inflammation initiated by obesity or IBD renders it maladaptive, triggering an influx of immune cells that, in turn, release proinflammatory adipokines, cytokines, and chemokines, resulting in local and systemic metabolic effects. Clinical data strongly link the accumulation of inflammatory MAT in the pathology of Crohn's disease through the development of \"creeping fat\", a fibrotic, immune-rich tissue that shields the inflamed bowel but can also exacerbate the condition. The inflammatory mediators produced by MAT and the mechanisms by which they aggravate IBD are not well understood. This review synthesizes recent advances in the understanding of the cellular complexity of MAT, emphasizing the bidirectional immune crosstalk between the intestine and the mesentery, and exploring how metabolic or microbial stress drives maladaptive transformation. Finally, we highlight therapeutic strategies that may preserve the reparative functions of MAT while limiting fibrogenic remodeling.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 2","pages":"e00081"},"PeriodicalIF":3.9,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13174941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147965881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune checkpoint blockade targets macrophage PD-1 to exacerbate metabolic dysfunction.","authors":"Zikuan Song, Christian Frezza","doi":"10.1097/IN9.0000000000000079","DOIUrl":"10.1097/IN9.0000000000000079","url":null,"abstract":"<p><p>Immune checkpoint inhibitor therapies induce metabolic dysfunction. A study by Wu et al now pinpoints macrophage programmed cell death protein 1 (PD-1) as a key molecular mediator of the anti-PD-1 treatment-triggered exacerbation of systemic metabolic disorders. Macrophage PD-1 blockade disrupts the moonlighting function of PD-1 in suppressing endoplasmic reticulum stress-mediated inflammatory responses, thereby impairing adipose tissue thermogenesis, reducing energy expenditure, and ultimately leading to systemic metabolic dysfunction.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 2","pages":"e00079"},"PeriodicalIF":3.9,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new twist in metabolic T cell exhaustion.","authors":"Konstantinos Aliazis, Vassiliki A Boussiotis","doi":"10.1097/IN9.0000000000000080","DOIUrl":"10.1097/IN9.0000000000000080","url":null,"abstract":"<p><p>Metabolic reprogramming of T lymphocytes has a decisive role in their activation, differentiation, and functional fate commitment. Metabolic reprogramming guides not only the generation of T effector and T memory cells but also the development of dysfunctional exhausted (T_EX) cells. A recent study by Haku et al published in <i>Nature Immunology</i> provides new insights into the role of mitochondria in regulating the metabolic capabilities of T_EX cells and their implications for antitumor immunity.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 2","pages":"e00080"},"PeriodicalIF":3.9,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13131908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1.","authors":"Rafael Moura Maurmann, Kierstin Davis, Negin Mosalmanzadeh, Brenda Landvoigt Schmitt, D Pence","doi":"10.1097/IN9.0000000000000078","DOIUrl":"10.1097/IN9.0000000000000078","url":null,"abstract":"<p><strong>Background: </strong>Severe coronavirus disease 2019 (COVID-19) is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin's anti-inflammatory effects are, however, unclear. We thus sought to investigate metformin's main interactions and their respective isolated effects in modulating monocyte inflammatory response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) stimulation.</p><p><strong>Methods: </strong>Classical human monocytes were isolated from healthy 18 to 40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis and inflammatory gene expression by quantitative polymerase chain reaction. Stimulated monocytes were either pretreated with metformin, rotenone, S1QEL, or A769662.</p><p><strong>Results: </strong>Monocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pretreatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither was complex I-specific reactive oxygen species scavenging. Conversely, A769662-induced AMP-activated protein kinase (AMPK) activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformin's mode of action upon S1 stimulation.</p><p><strong>Conclusions: </strong>In summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformin's anti-inflammatory effect.</p>","PeriodicalId":73349,"journal":{"name":"Immunometabolism (Cobham (Surrey, England))","volume":"8 1","pages":"e00078"},"PeriodicalIF":3.9,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12940627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147328408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}