Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis

• Published in: Rheumatology (Oxford, England) Vol. 60; no. 1; pp. 420 - 429
• Main Authors: Katsuyama, Takayuki, Li, Hao, Krishfield, Suzanne M, Kyttaris, Vasileios C, Moulton, Vaishali R
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 05.01.2021
• Subjects: Animals; Basic and Translational Science; Cell Differentiation - physiology; Flow Cytometry; Humans; Interferon-gamma - metabolism; Lupus Nephritis - genetics; Lupus Nephritis - immunology; Lupus Nephritis - metabolism; Mice; Mice, Knockout; rho GTP-Binding Proteins - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Transcription Factors - metabolism; RhoH; systemic lupus erythematosus; cytokines; T cells; SRSF1
• ISSN: 1462-0324; 1462-0332
• DOI: 10.1093/rheumatology/keaa300

Abstract Objective CD4 T helper 1 (Th1) cells producing IFN-γ 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-γ production, Th1 differentiation and experimental nephritis. Methods T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ 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-γ. 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-γ 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.