Mast cell tryptase-PAR2 axis promotes ovarian fibrosis through RNF152-mediated stabilization of Bcl-xL

Abstract

Ovarian fibrosis is a basic histologic feature of premature ovarian insufficiency(POI), which poses a great threat to women of reproductive age. Collagen abundance in ovarian theca-stroma cells contributes to ovarian fibrogenesis. However, the role and mechanism of mast cells in the development of POI have not yet been determined. Our study for the first time found that tryptase secreted by activated mast cells induced COL1A1 and COL1A2 production, two subunits of collagen I in mouse theca–stroma cells by protease-activated receptor-2 signaling. Inhibition of PAR2 or Bcl-xL attenuated the increases of COL1A1 and COL1A2 caused by tryptase. In addition, knockdown of RNF152 reversed the downregulation of collagen production caused by si-Bcl-xL. Clinically, tryptase levels in serum and follicular fluid were higher in both bPOI and POI patients than in controls. Tryptase concentrations in serum and follicular fluid were positively associated with follicle stimulating hormone(FSH) and negatively associated with anti-Müllerian hormone (AMH). Cromolyn sodium, a mast cell stabilizer, reduces collagen I production, but has no effect on hormone synthesis and follicle number in a cisplatin-induced POI mouse model. Our findings shed new insights into the biological function of tryptase in ovarian fibrosis and POI.