Abstract
BackgroundIt is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease. In experimental autoimmune uveitis (EAU) induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in mice, we have previously reported that intraocular inflammation was initiated by infiltrating IRBP-specific T cells that directly interacted with retinal cells and resulted in the active release of high mobility group box 1 (HMGB1), an important member of damage associate molecular patterns (DAMPs). Furthermore, blockade of HMGB1 in our murine model reduced intraocular inflammation via suppression of IRBP-specific T cell functions. These results have demonstrated that HMGB1 is an early and critical mediator of induction of intraocular inflammation. The present study identified the cell surface molecule that triggers HMGB1 secretion.MethodsRetinal explants from Fas-deficient (Faslpr) and wild-type (Wt) C57BL/6 (B6) mice were cultured with activated IRBP 1–20 peptide-specific T cells or with a Fas-activating antibody (Jo2), and then the level of HMGB1 in culture supernatants were detected by ELISA. In addition, released HMGB1 was examined in the eye of Faslpr and Wt mice after IRBP-specific T cell transfer. Uveitis was evaluated in the IRBP-specific T cell transferred Faslpr mice after recombinant HMGB1 was restored within the eye and in the IRBP-specific T cell transferred Wt mice after they were treated with a Fas antagonist (Met12).ResultsIn contrast to retinal explants from Wt mice, those from Faslpr mice did not release HMGB1 after exposure to IRBP-specific T cells or to Jo2. The release of HMGB1 by Wt retinal explants was suppressed by Met 12. Moreover, after IRBP-specific T cell injection, Faslpr mice did not release HMGB1 in the eye or develop EAU, but intravitreous injection of HMGB1 resulted in intraocular inflammation. Finally, tEAU in Wt mice was attenuated by local treatment with Met 12. Unlike HMGB1, Fas-induced IL-1 and IL-18 were not essential for tEAU induction.ConclusionOur results show that interaction of retinal cells with infiltrating uveitogenic T cells leads to rapid release of HMGB1 via the Fas/FasL inflammatory signaling pathway.
Highlights
It is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease
Our results show that interaction of retinal cells with infiltrating uveitogenic T cells leads to rapid release of high mobility group box 1 (HMGB1) via the Fas/FasL inflammatory signaling pathway
In a search for damage associate molecular patterns (DAMPs) that interact with Toll-like receptors (TLRs)/ myeloid differentiation factor 88 (MyD88) in activated IRBP-specific T cell-induced EAU (tEAU), we previously showed that HMGB1 is an early and critical mediator of interphotoreceptor retinoid-binding protein (IRBP)-specific T cell-induced intraocular inflammation, since HMGB1 antagonists reduce ocular inflammation by suppression of uveitogenic T cell functions, such as IRBPspecific T cell proliferation and cytokine production [13]
Summary
It is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease. In experimental autoimmune uveitis (EAU) induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in mice, we have previously reported that intraocular inflammation was initiated by infiltrating IRBP-specific T cells that directly interacted with retinal cells and resulted in the active release of high mobility group box 1 (HMGB1), an important member of damage associate molecular patterns (DAMPs). Danger signals are initiated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) [10, 11], the latter being actively secreted from inflammatory or stressed cells or passively released from damaged apoptotic or necrotic cells Both PAMPs and DAMPs can be recognized by pattern-recognition receptors, including TLRs, NODlike receptors, retinoic acid-inducible gene-like receptors, and receptors for advanced glycation end products [10, 11]. The importance of DAMPs in T cell-mediated uveitis was identified as a result of our observation that in the chronic uveitis mouse model induced by transfer of IRBP-specific T cells (tEAU), a model induced without the use of microbial products and resembling human chronic uveitis, mice lacking MyD88 (MyD88−/−) are completely resistant to induction of tEAU [13]
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