IL-17 induces salivary gland secretory dysfunction via modulating calcium influx in primary Sjögren's syndrome

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by secretory dysfunction and inflammation in salivary glands (SG). Currently, the pathogenesis of SS is still unclear. Although previous studies indicated the involvement of IL-17 in SS pathogenesis, how IL-17 affects SG hypofunction remains largely unclear. In this study, we explored the roles of IL-17 in SG secretory dysfunction and the underlying mechanisms during SS development. IL-17-producing cells were identified in labial gland biopsies from primary SS patients and the numbers were negatively correlated with saliva flow rates. Using murine experimental SS (ESS) model, we observed ameliorated disease development in IL-17 knockout (KO) and IL-17 receptor C (IL-17RC) KO mice compared with wild type (WT) controls. Moreover, WT ESS mice displayed markedly increased numbers of IL-17-producing T cells and Th17 cells in SG tissues and draining lymph nodes when compared with naïve mice. Notably, the chimeric mice with IL-17RC deficiency restricted in non-hematopoietic cells exhibited improved saliva secretion and ameliorated tissue inflammation when compared with WT controls. Acini from ESS mice showed decreased acetylcholine-induced calcium movement whereas IL-17 diminished the acetylcholine-induced store-operated calcium entry (SOCE) in cultured primary SG epithelial cells. Moreover, IL-17 treatment reduced expression of transient receptor potential channel 1 (TRPC1), the key ion channel for calcium influx in SOCE. Furthermore, retrograde cannulation of IL-17-neutralizing antibody into SG improved saliva secretion in ESS mice. Collectively, the results revealed the pathophysiological roles of IL-17 in SG secretory dysfunction, indicating that IL-17 might be a promising target for treating SS.