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Atsunobu Takeda, Takeru Yoshimura, Sayaka Hirakawa, Toshio Hisatomi, Yasuhiro Ikeda, Hiroshi Enaida, Yuji Oshima, Koh-hei Sonoda, Tatsuro Ishibashi; Pivotal roles of P2RX7 in the induction of Th1 and Th17 responses in experimental autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):97.
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© ARVO (1962-2015); The Authors (2016-present)
Murine experimental autoimmune uveitis (EAU) is a model of human uveitis. Both Th1 cells and Th17 cells play crucial roles in the generation of tissue damage in EAU. P2RX7, which is a heterotrimeric guanine nucleotide-binding protein, is hypothesized to control TCR-dependent T cell activation. However, roles of P2RX7 in uveitis remain unclear. The purpose of this study is to investigate the roles of P2RX7 in EAU.
Mice (either wild-type (WT) or P2rx7-deficient (P2rx7 KO) mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 1-20 previously described. Severity of EAU was evaluated clinically and histopathologically. The induction of IRBP-specific 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), which is an antagonist for P2RX7, in EAU were assessed by clinical score and ELISA for IRBP-specific cytokines production in draining lymph nodes in WT mice.
The severity of EAU in P2rx7 KO was diminished as compared with that in WT clinically and histopatholoically. The induction of IRBP-specific both IFN-γ and IL-17 in P2rx7 KO on day 18 was less than that in WT. The up-regulation of surface expression of activation markers such as CD25, CD44, and CD69 in response to TCR stimulation in P2rx7 KO was decreased as compared with that in WT mice. Furthermore, neutralization of P2RX7 by BBG in vivo suppressed clinical scores during the entire phase. IRBP-specific IFN-γ and IL-17 induction in BBG-treated mice were significantly lower in BBG-treated mice than those in vehicle-treated mice.
These results suggest that P2RX7 is a novel preventative therapeutic target for uveitis by suppression of both Th1 and Th17 responses.
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