Metabolic Reprogramming of Pathogenic CD4⁺T Helper Cells Attenuates Inflammatory Bowel Disease Pathogenesis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 20, 2025

BACKGROUND & AIMS CD4 + T helper 1 (Th1) cells are involved in human inflammatory bowel disease (IBD) pathogenesis; however, mechanisms governing the persistent function of these unclear, leading us to examine how metabolism governs Th1 cell-induced IBD. METHODS supplemented with methyl pyruvate (MePyr) were analyzed define enforced mitochondrial and subsequent glycogen synthase kinase 3β (GSK3β) deactivation reprogram cellular state. Re-analysis inflamed ileal single-cell RNA sequencing dataset from Crohn’s patients was performed assess non-Treg cell metabolic gene signature. We assessed capacity a repurposed GSK3β inhibitor restrain pathogenic cell-driven murine colitis. RESULTS Effector exhibit distinct program exemplified by glucose-driven glycolysis but low respiration. MePyr deactivates GSK3β, glycolysis, histone H3 acetylation on cytokine promoter region, resulting reduced interferon-γ (IFN-γ) tumor necrosis factor-α (TNF-α) expression concomitant gain regulatory cell-like program. inhibition LY2090314 mirrored anti-inflammatory effect manner reversible acetate supplementation, implying that potentially sustains glycolysis-derived acetyl-coenzyme A needed for response. Interleukin-21 exacerbates response maintaining GSK3β-driven glycolytic The signature downregulated or vitro is enriched refractory patients. retrains colitis mice. CONCLUSIONS impairs GSK3β-mediated immune may mitigate Graphical abstract

Язык: Английский

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Roles of the gut microbiota in immune-related adverse events: mechanisms and therapeutic intervention

Nature Reviews Clinical Oncology, Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Язык: Английский

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Commensal fungi, a force to be reckoned with

Cell Host & Microbe, Год журнала: 2025, Номер 33(1), С. 6 - 8

Опубликована: Янв. 1, 2025

Язык: Английский

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Improving bench-to-bedside translation for acute graft-versus-host disease models

Disease Models & Mechanisms, Год журнала: 2025, Номер 18(2)

Опубликована: Фев. 1, 2025

ABSTRACT The transplantation of allogeneic hematopoietic stem cells is a potentially curative treatment for hematological malignancies, inherited blood disorders and immune deficiencies. Unfortunately, 30-50% patients receiving will develop life-threatening inflammatory disease called acute graft-versus-host (aGVHD). In with aGVHD, graft-associated T cells, which typically target the skin, intestinal tract liver, can also damage lungs lymphoid tissue. Damage to tissue creates prolonged immunodeficiency that markedly increases risk infections bleeding, resulting in considerable morbidity mortality. Although mouse models aGVHD have been instrumental our understanding this condition's pathogenesis, translation preclinical data into new more effective treatments human has limited reasons remain be fully understood. However, evidence suggests factors associated likely contribute these unsatisfactory results. Review, we identify discuss specific inherent may limit patient treatment, suggest how improve translatability models.

Язык: Английский

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Rewilding catalyzes maturation of the humoral immune system

Science Advances, Год журнала: 2025, Номер 11(10)

Опубликована: Март 7, 2025

Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, impact environment on B cell compartment has not been investigated detail. Here, we performed in-depth examination cells following rewilding, controlled release inbred into outdoor enclosure. In rewilded mice, observed circulation increased signs maturation, alongside heightened germinal center responses within secondary lymphoid organs. Rewilding also expanded gut, was accompanied by elevated systemic levels immunoglobulin G (IgG) and IgM antibodies reactive microbiota. Our findings indicate that exposing more natural enhances development better reflect free-living mammals.

Язык: Английский

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An updated review on immune checkpoint inhibitor-induced colitis: epidemiology, pathogenesis, treatment strategies, and the role of traditional Chinese medicine

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 17, 2025

Immune checkpoint inhibitor-induced colitis (irColitis) is a common and severe adverse reaction to immune inhibitors (ICIs), significantly impacting the treatment outcomes quality of life cancer patients. Epidemiological studies indicate that incidence irColitis associated with factors such as type ICIs, patient's gender, age, medical history. Although exact pathophysiology remains unclear, thought be related system activation dysregulation, gut microbiota imbalance, impaired epithelial barrier function. This review summarized epidemiology, clinical presentation, diagnostic criteria, pathogenesis irColitis. Additionally, standard novel therapeutic strategies irColitis, including corticosteroids, biologics, interventions, more importantly potential application Traditional Chinese Medicine (TCM). Future researches call for deeper mechanistic investigations, development biomarkers, reveal integration TCM therapies within individual immunotherapy frameworks.

Язык: Английский

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Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease

Опубликована: Апрель 11, 2025

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator T cell activation. However, establishing direct link between CTLA-4 has been challenging due to the early lethality knockout mice. In this study, we identified zebrafish Ctla-4 homolog investigated its role maintaining immune homeostasis generating Ctla-4-deficient ( ctla-4 −/− ) line. These mutant exhibited reduced weight, along with impaired barrier integrity lymphocytic infiltration their intestines. Transcriptomics analysis revealed upregulation inflammation-related genes, disturbing system homeostasis. Moreover, single-cell RNA-sequencing indicated increased Th2 cells interleukin 13 expression, decreased innate lymphoid upregulated proinflammatory cytokines. Additionally, diversity altered composition microbiota. All these phenotypes closely resemble those found mammalian IBD. Lastly, supplementation Ctla-4-Ig successfully alleviated mutants. Altogether, our findings demonstrate pivotal they offer substantial evidence linking establish novel model for investigating both pathogenesis potential treatments.

Язык: Английский

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Gut microbiota — bidirectional modulator: role in inflammatory bowel disease and colorectal cancer

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 30, 2025

The gut microbiota is a diverse ecosystem that significantly impacts human health and disease. This article focuses on how the interacts with inflammatory bowel diseases colorectal tumors, especially through immune regulation. plays role in system development regulation, while body's status can also affect composition of microbiota. These microorganisms exert pathogenic effects or correct disease states gastrointestinal actions toxins secretions, inhibition responses, DNA damage, regulation gene expression, protein synthesis. its metabolites are essential progression tumors. complexity bidirectionality this connection tumors inflammation might render it new therapeutic target. Hence, we explore strategies for microbiota, highlighting potential probiotics fecal transplantation to restore adjust microbial community. Additionally, address challenges future research directions area concerning

Язык: Английский

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Bolstering CD8+ T Cells’ Antitumor Immunity: A Promising Strategy to Improve the Response to Advanced Prostate Cancer Treatment

Biology, Год журнала: 2025, Номер 14(5), С. 544 - 544

Опубликована: Май 14, 2025

Prostate cancer is among the most frequently diagnosed and deadly cancers men in Western world. It typically classified as an immune "cold" tumor due to its sparse cell presence limited immunogenic response. Recent research has revealed significant role of cells, especially CD8+ T both prostate progression treatment efficacy. This review integrates recent findings provide a comprehensive overview current understanding dynamics discusses emerging strategies improve outcomes. The ongoing exploration new molecular targets development innovative immunotherapeutic approaches hold promise for more effective management cancer, particularly context advanced resistant forms disease.

Язык: Английский

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Advanced Biomaterials and Delivery Modalities to Alleviate Cancer Therapy-Induced Inflammation

Biomaterials, Год журнала: 2025, Номер unknown, С. 123419 - 123419

Опубликована: Май 1, 2025

Язык: Английский

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