SIGIRR Deficiency Contributes to CD4 T Cell Abnormalities by Facilitating the IL1/C/EBPβ/TNF-α Signaling Axis in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant T-cell activation plays a key role in the initiation and perpetuation of the disease. The factors that trigger T cell abnormalities in these inflammatory processes are incompletely understood. SIGIRR (single immunoglobulin IL-1R-related receptor) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. Here, we identified defects in SIGIRR in activated CD4 T cells as an underlying dysregulation. SIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing, and its expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA) attributed to unleashed tumor necrosis factor (TNF)-α production in antigen-specific CD4 T cells. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis. Taken together, SIGIRR deficiency in RA CD4 T cells raised the possibility that receptor interference can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.