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Simvastatin alleviates ConA-induced autoimmune hepatitis by inhibiting CD4+T cell activation via calcium-NFATC3 pathway

ABSTRACT: The mevalonate pathway plays a crucial role in various immune disease and Hmgcr is the key enzyme of this pathway. In addition, simvastatin, as an inhibitor of Hmgcr , also exhibits therapeutic potential for acute liver injury such as APAP-induced toxicity and hepatic ischemia-reperfusion injury (HIRI). However,its effect in ConA-induced acute liver injury remains unclear.

ORGANISM(S): Mus musculus

PROVIDER: GSE301394 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Objective: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with metabolic syndrome (MetS) in humans and hepatic effects similar to non-alcoholic fatty liver disease through activation of the aryl hydrocarbon receptor (AHR) pathway. Dysregulation of cholesterol homeostasis, an aspect of MetS, is linked to NAFLD pathogenesis, and TCDD exposure is also linked to the suppression of genes that encode key cholesterol biosynthesis steps and changes in serum cholesterol levels. In a previous experiment, treating mice with TCDD in the presence of simvastatin, a 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) competitive inhibitor, increased toxicity in male mice, compared to TCDD alone. The aim of this study was to deduce a possible mechanism(s) for this increased liver injury. Methods: Male C57Bl/6 mice were treated with vehicle control or TCDD via oral gavage and were fed either standard or simvastatin-laced chow. Single nuclei RNA sequencing (snRNASeq) was performed in mouse liver to investigate the impact of treatment on distinct liver cell (sub)types that may explain differences in pathology between treatments. Results: We demonstrated that co-treated mice experienced exacerbated wasting and increased AHR activation compared to TCDD alone. Furthermore, relative proportions of cell (sub)types were different between TCDD alone and co-treated mice including important mediators of NAFLD progression such as hepatocytes and Kupffer cells. Co-treated mice promoted upregulation of lipid metabolism in hepatocytes, which is consistent with decreased fat accumulation seen in previous studies. Interestingly, the proportion of plasmacytoid dendritic cells (pDCs) increased in only co-treated mice, which may play an important role in the differences in immune cell infiltration between treatment groups. Conclusions: Our results suggest simvastatin co-treatment promotes a worse prognosis of TCDD-induced injury in mice and alterations in immune infiltration between treatments may influence liver injury severity.

Project description:Background: Microvascular injury and increased vascular leakage are prominent features of the radiation-induced lung injury (RILI) which follows cancerâ??associated thoracic irradiation. The mechanisms of RILI are incompletely understood and therapeutic strategies to limit RILI are currently unavailable. We established a murine model of radiation pneumonitis in order to assess mechanism-based therapies for RILI-induced inflammation and vascular barrier dysfunction. Based on prior studies, we investigated the therapeutic potential of simvastatin as a vascular barrier protective agent in RILI. Methods: C57BL6/J mice receiving single dose exposure to 18, 20, 22, or 25 Gy, (n=10/group) were temporally assessed (4-12 weeks) for cellular and biochemical indices of injury present in both bronchoalveolar lavage (BAL) and lung tissues (cytokines, tyrosine nitrosylated proteins, leukocytes, extravasation of Evans blue dye or EBD, BAL albumin, histology). In specific experiments, irradiated mice (25Gy) received simvastatin (10 mg/kg) via intraperitoneal injection three times a week (pre and post irradiation) for 2- 6 weeks post irradiation. Results. Acute RILI evolved in a dose- and time-dependent fashion. Mice irradiated with 25Gy exhibited modest increases in BAL leukocytes but significant increases in BAL IL-6 (p=0.03) and TNF-a (p=0.01) at 4 weeks compared to controls. Increases in BAL nitrotyrosine content peaked at 6 weeks (p=0.03) and was accompanied by marked nitrotyrosine immunostaining in lung tissues. Indices of increase lung vascular permeability such as EBD extravasation, BAL protein and BAL albumin significantly increased over time beginning at 6 weeks (p>0.002 all) with histological evidence of severe edema formation and airway inflammation. Simvastatin- treated irradiated mice were noted to exhibit marked attenuation of vascular leak with significantly decreased BAL protein (p=0.01) and inflammatory cell infiltration (50% reduction). Conclusion: Simvastatin is a potentially important therapeutic strategy to limit RILI and may influence radiation associated morbidity and mortality. We used microarrays to detail the global programme of gene expression induced by radiation in Wild type and the protection of SIMVA Experiment Overall Design: animals were treated by Vehical, Radiation (25Gy), SIMVA(10mg/kg), or both.

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Simvastatin alleviates ConA-induced autoimmune hepatitis by inhibiting CD4+T cell activation via calcium-NFATC3 pathway

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