IFITM1 aggravates ConA-Induced autoimmune hepatitis by promoting NKT cell activation through increased AMPK-Dependent mitochondrial function

• Published in: International immunopharmacology 2025-01, Vol.144, p.113692, Article 113692
• Main Authors: Sun, Jie, Xu, Haozhe, Li, Buer, Deng, Wanqing, Han, Xiaotong, Zhong, Xinjie, Zhu, Jingjing, Jiang, Yuan, Wang, Zeyu, Zhang, Dong, Sun, Guangyong
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Autoimmune Hepatitis; Concanavalin A; Cytokines - metabolism; Hepatitis, Autoimmune - immunology; Humans; IFITM1; Liver - immunology; Liver - pathology; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Natural Killer T-Cells - immunology; NKT Cells
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113692

[Display omitted] •IFITM1 is elevated expressed in the ConA-induced immune hepatitis.•Knockout of IFITM1 alleviates intrahepatic damage and inflammatory responses.•IFITM1 regulates the survival, proinflammatory and cytotoxic function of NKT cells.•IFITM1 promotes NKT cells function by enhancing mitochondrial energy metabolism. Although interferon-induced transmembrane 1 (IFITM1) is known for its crucial role in antiviral immunity, its involvement in autoimmune hepatitis (AIH) remains largely unexplored. In this study, we observed that IFITM1 expression is markedly upregulated in a Concanavalin A (ConA)-induced AIH model, with particularly high and markedly elevated expression in natural killer T (NKT) cells. To further understand the role of IFITM1, we examined the responses of IFITM1−/− mice in a model of ConA-induced liver injury. In comparison to wild-type mice, IFITM1−/− mice exhibited reduced sensitivity in this model, as evidenced by significantly ameliorated necrosis areas, lower serum aminotransferase levels, a reduced number of intrahepatic NKT cells, and decreased expression of inflammatory factors, such as IL-1β, IL-6, IFN-γ and TNF-α. Notably, by using IFITM1-GFP mice and IFITM1−/− mice, we demonstrated that IFITM1 expression in NKT cells is crucial for their proliferation, proinflammatory cytokine production, and cytotoxic functions. Furthermore, analysis of single-cell RNA sequencingdata revealed that IFITM1 is essential for mitochondrial function, which is mediated by the AMP-activated protein kinase (AMPK) pathway. We also validated the importance of IFITM1 for the AMPK pathway and mitochondrial ATP synthesis in vivo. Together, our findings elucidate that IFITM1 could regulate NKT cell activation and survival by promoting mitochondrial function during AIH.