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Guomin Jiang, Amir Hajrasouliha, Henry Kaplan, Hui Shao; Fas-dependent release of high-mobility group protein B1 (HMGB1) in the eye is critical for the development of experimental autoimmune uveitis (EAU) initiated by uveitogenic T cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2028.
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We have previously reported that HMGB1, an important member of damage-associated molecular patterns (DAMPs), is an early and critical mediator in the eye in response to transferred uveitogenic T cells and that transfer of uveitogenic T cells into Fas deficient (lpr) mice did not induce HMGB1 release by retinal tissue cells nor result in intraocular inflammation. In this study, we wanted to test if HMGB1 release in the eye is Fas-dependent.
: Retinal explants from Fas-deficient (Faslpr) and wild-type (wt) C57BL/6 (B6) mice were cultured with a Fas receptor agonist (Jo2 Ab) or interphotoreceptor retinoid-binding protein (IRBP) 1-20 peptide-specific T cells, and then the level of HMGB1 in culture supernatants were detected by ELISA. In addition, uveitis was evaluated after IRBP-specific T cell transfer into both Faslpr mice intra-vitreous injected with recombinant HMGB1and in wt B6 mice intra-vitreous injected with a Fas signaling antagonist (Met12).
Compared to Faslpr retinal explants, high level of HMGB1 was detected in the culture supernatants of wt retinal explants cocultured with either IRBP-specific T cells or Jo2 Ab for 2 and 4 hours. The increased HMGB1 release was suppressed by Fas signaling pathway inhibitor Met12. Moreover, IRBP-specific T cells induced uveitis in Faslpr mice intravitreously injected with HMGB1, whereas, uveitis induced by IRBP-specific T cells in wt B6 mice was attenuated by Met12 treatment.
: Except the fact that Fas could mediate apoptotic cell death, we have found that Fas signaling is also involved in HMGB1 secretion from intact retinal cells in response to uveitogenic T cells. Blockade of Fas signaling pathway reduced HMGB1 release, thus, suppressing the development of uveitis. Met12, a Fas antagonist, might be a potential alternative for the treatment of autoimmune uveitis in man.
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