Tripartite motif-containing 21 (TRIM21) is a cytoplasmic protein with E3 ubiquitin ligase activity. Although autoantibodies against TRIM21 are frequently detected in patients with systemic lupus erythematosus (SLE), its role in disease pathogenesis remains unclear. Here we demonstrate that TRIM21 directly interacts with the stimulator of interferon genes (STING) to regulate type I interferon (IFN) production. In both induced and spontaneous murine models of lupus, TRIM21 deficiency exacerbated lupus-like pathology and heightened IFN production after STING activation. By contrast, TRIM21 overexpression attenuated autoimmunity in lupus-prone mice. Mechanistically, TRIM21 binds to STING and promotes its degradation via the ubiquitin-proteasome pathway. In patients with SLE, TRIM21 expression levels inversely correlated with STING expression, type I IFN levels and autoantibody titers. These findings suggest that targeting the TRIM21-STING axis may offer a therapeutic strategy to reduce type I IFN production in SLE.
© 2025. The Author(s).

Food allergy (FA) has received increased attention in recent years. Multiple studies have highlighted the crucial role of short-chain fatty acids (SCFAs) in the development of IgE-mediated FA. Here, a case-control approach was employed to analyze SCFAs profiles in children with FA, while an ovalbumin (OVA)-sensitized mouse model was utilized to explore the underlying mechanism by which SCFAs mitigate FA. Children with food-sensitized tolerance (FST) (n = 20) or FA (n = 20), and healthy controls (HC) (n = 20) were recruited to analyze SCFAs profiles. The HC group exhibited higher SCFAs levels in fecal samples than the FST, FA, and FST + FA groups. Data from an OVA-sensitized mouse model showed that butyrate exhibited a more significant effect on reducing allergic reactions compared to other SCFAs. Compared to the negative control group, OVA-induced oxidative stress (OS) triggered excessive Notch signaling activation, which subsequently impaired both tight junctions integrity and mucosal barrier function in murine intestinal epithelial cells (IECs). Gut dysbiosis induced mucus layer erosion, thereby elevating IECs exposure to food antigens and OS, which potentiated Notch signaling activation. However, butyrate counteracted this loop by restoring microbiota structure and suppressing reactive oxygen species (ROS)/Notch cascades. Strikingly, low-dose butyrate (0.25-1 mM) protected rat small intestine crypt epithelial cells (IEC-6) by inhibiting ROS, whereas high-dose (2-5 mM) exacerbated oxidative injury and triggered activation of Notch signaling. Our study revealed the potential molecular mechanisms through which butyrate alleviates food allergy, providing a potential therapeutic strategy for its management.
© 2025 The Author(s). iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.

The gene associated with the retinoid-IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing mitophagy.
© 2024. The Author(s).

Abstract Background Atherosclerosis involves inflammatory and thrombotic mechanisms, to which platelets, CD4+ T effector cells, and transforming growth factor β (TGFβ) all contribute importantly. Platelets are the principal source of circulating TGFβ, which profoundly regulates CD4+ T effector cell responses. The impact of platelet-derived TGFβ on atherosclerosis is, however, unknown. Objectives The present work investigated how platelet-specific TGFβ-deficiency impacts CD4+ T effector cell responses and atherogenesis. Methods Murine platelet-selective TGFβ-deficiency (plt-TGFβ−/−) was created by a Pf4-Cre approach, and an atherosclerotic mouse model was established by functional abrogation of Ldlr and 10–15 weeks of a high-fat diet in plt-TGFβ−/− mice and their non-plt-TGFβ−/− littermates. Results En face Oil Red O staining of the aorta showed more atherosclerotic lesion formation in plt-TGFβ−/− mice, with significant increases in both lesion size and lesion coverage of the total aortic area. Cryosections of the aortic root confirmed the aggravation of atherogenesis. Platelet-derived TGFβ deficiency increased circulating platelets and plasma levels of total cholesterol, LDL-cholesterol, and triglycerides after a 10 or 15 week high-fat diet period. RNA sequencing and proteomic analyses of the aorta showed signs of CD4+ T effector cell and macrophage activation in plt-TGFβ−/− mice. Conclusions Platelet-specific TGFβ deficiency aggravates atherosclerosis, via increasing arterial inflammation and plasma levels of cholesterol. Our findings demonstrate that platelet-derived TGFβ is prominently athero-protective.

Though an increased risk of atherosclerosis is associated with anti-CTLA-4 antibody therapy, the underlying mechanisms remain unclear.
C57BL/6 mice were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody twice a week for 4 weeks, after being injected with AAV8-PCSK9 and fed a Paigen diet (PD). The proportion of aortic plaque and lipid accumulation were assessed using Oil Red O staining, while the morphology of atherosclerotic lesions was analyzed with hematoxylin and eosin staining. Collagen content was evaluated through Picrosirius Red (PSR) staining, while inflammatory cell infiltration was examined with immunofluorescence staining. CD4+ T cells secreting IFN-γ and IL-4, which represent Th1 and Th2 cells respectively, were detected by flow cytometry and real-time PCR. Protein levels of p-IκBα, IκBα, p-p65, and p65 were determined by Western blot.
Inhibiting CTLA-4 exacerbated PD-induced plaque progression and promoted CD4+ T cell infiltration in the aortic root. The anti-CTLA-4 antibody promoted CD4+ T cell differentiation toward the Th1 type, as indicated by an increase in the Th1/Th2 ratio. Compared to the anti-IgG group, treatment with anti-CTLA-4 antibody significantly elevated the protein levels of p-IκBα and p-p65, as well as the mRNA levels of TNF-α, IL-6, ICAM-1, and VCAM-1. Inhibiting the NF-κB signaling pathway attenuated the overall pathological phenotype induced by the anti-CTLA-4 antibody treatment.
Anti-CTLA-4 treatment promotes the progression of atherosclerosis by activating NF-κB signaling and modulating the Th1/Th2 balance. Our results provide a rationale for preventing and/or treating atherosclerosis accelerated by anti-CTLA-4 antibody therapy in cancer patients.
© 2024 The Authors.