Crucial role of P2Xreceptor for effector T cell activation in experimental autoimmune uveitis.

Abstract

PURPOSE: To investigate the roles of P2X7 receptors (P2RX7) in the pathogenesis of experimental autoimmune uveoretinitis (EAU). STUDY DESIGN: Experimental. METHODS: Either wild-type (P2rx7) or P2rx7-deficient (P2rx7) mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 1-20. Severity of EAU was evaluated clinically and histopathologically. The induction of IRBP-specific proliferation and cytokines in draining lymph nodes was assessed by enzyme-linked immunosorbent assays (ELISA). The frequency of activation markers was examined by flow cytometry. Furthermore, inhibitory roles of systemic administration of Brilliant Blue G (BBG), an antagonist for P2RX7, in EAU were also assessed in the wild-type mice. RESULTS: The severity of EAU in P2rx7mice was reduced as compared with that in P2rx7mice, both clinically and histopathologically. IRBP-specific proliferation in P2rx7on day 16 was slightly decreased compared to that in P2rx7mice. The induction of IRBP-specific interferon (IFN)-γ and interleukin (IL)-17 in P2rx7mice on day 16 was lower than that in P2rx7mice. The up-regulation of surface expression of activation markers such as CD25, CD44, and CD69 in response to TCR stimulation in P2rx7mice was decreased as compared with that in P2rx7mice. Furthermore, neutralization of P2RX7 in vivo by BBG suppressed EAU clinically and histopathologically. IRBP-specific IFN-γ and IL-17 induction in BBG-treated mice was significantly lower than that in vehicle-treated mice. CONCLUSION: The results suggest that P2RX7 is a novel preventative therapeutic target for uveitis as it suppresses the effector functions of both Th1 and Th17 cell responses.