| First Author | Katsuyama T | Year | 2021 |
| Journal | Rheumatology (Oxford) | Volume | 60 |
| Issue | 1 | Pages | 420-429 |
| PubMed ID | 32810232 | Mgi Jnum | J:316330 |
| Mgi Id | MGI:6835737 | Doi | 10.1093/rheumatology/keaa300 |
| Citation | Katsuyama T, et al. (2021) Splicing factor SRSF1 limits IFN-gamma production via RhoH and ameliorates experimental nephritis. Rheumatology (Oxford) 60(1):420-429 |
| abstractText | OBJECTIVE: CD4 T helper 1 (Th1) cells producing IFN-gamma contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-gamma production, Th1 differentiation and experimental nephritis. METHODS: T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-gamma production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. RESULTS: Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-gamma. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. CONCLUSION: Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-gamma production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms. |
