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

Takayuki Katsuyama, Hao Li, Suzanne M. Krishfield, Vasileios C. Kyttaris, Vaishali R. Moulton

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Objective: CD4 T helper 1 (Th1) cells producing IFN-γcontribute 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-γproduction, Th1 differentiation and experimental nephritis. Methods: T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γproduction 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-γproduction and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.

Original languageEnglish
Pages (from-to)420-429
Number of pages10
JournalRheumatology and Rehabilitation
Volume60
Issue number1
DOIs
Publication statusPublished - Jan 1 2021
Externally publishedYes

Keywords

  • RhoH
  • SRSF1
  • T cells
  • cytokines
  • systemic lupus erythematosus

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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