USP18-mediated protein stabilization of NOTCH1 is associated with altered Th17/Treg cell ratios and B cell-mediated autoantibody secretion in Sjögren syndrome.

Abstract

Sjögren Syndrome (SS) is a chronic inflammatory autoimmune disease characterized by lymphocytic infiltration of exocrine glands. This study, based on bioinformatics predictions, investigates the biological functions of ubiquitin specific peptidase 18 (USP18) and notch receptor 1 (NOTCH1) in T helper 17 (Th17) and regulatory T (Treg) cell imbalance and B cell activity in SS. USP18 and NOTCH1 were highly expressed in peripheral blood mononuclear cells (PBMCs) of SS patients and the PBMCs of NOD mice compared to the controls. Adenovirus-mediated knockdown of USP18 significantly enhanced the salivary flow rate of NOD mice while reducing lymphocyte infiltration in mouse salivary ligand tissues. In addition, it decreased the proportions of Th17 cells while increasing the proportions of Treg cells. USP18 enhanced NOTCH1 protein stability through de-ubiquitination modification. In the presence of USP18 knockdown, the NOTCH1 upregulation restored the predominance of Th17 cells in mice. In B cells isolated from PBMCs, the production of B cell autoantibodies was decreased by USP18 silencing but enhanced by NOTCH1 upregulation. In summary, this study demonstrates that USP18-mediated protein stabilization of NOTCH1 is correlated with Th17/Treg cell imbalance and B cell activity during SS development.