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Holly Lallman Rosenzweig, Brieanna Brown, Paige Snow, Emily Vance, Phyllis Silver, Rachel R Caspi, Ellen J Lee; Mincle activation and Syk/Card9 signaling axis are central to development of autoimmune disease of the eye. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
The innate immune receptors responsible for induction of eye-specific autoreactive T cells remain poorly defined. We recently identified Mincle, a C-type lectin receptor (CLR) vital to host defense that signals through Syk and Card9 to mediate innate immune cell activation, as essential in induction of ocular autoimmunity, using experimental autoimmune uveitis (EAU). Here, we further delineate molecular and cellular factors involved in orchestrating this Mincle-dependent mechanism.
EAU was induced in C57BL/J mice deficient in Card9 or Mincle (encoded by Clec4e) by immunization with interphotoreceptor retinoid-binding protein (IRBP). Uveitis was evaluated by fundus imaging and histology. The synthetic Mincle agonist TDB (trehalose-6-6’-dibehenate) was used in lieu of CFA. Syk was pharmacologically inhibited by piceatannol (given i.p., q4d, d0-16). To define the cellular source of Card9 and Mincle-activated responses, studies with bone marrow (BM) chimeras were performed. In addition, Cre-Lox recombination was used to generate conditional KO mice with CD11c+ dendritic cells (DCs) lacking Syk.
Mice immunized with Mincle agonist TDB developed uveitis (p<0.05; n=8 mice/group). The effect of TDB required Mincle and its downstream CLR signaling adaptor, Card9, as EAU was significantly reduced in the absence of either molecule (p<0.05, n=10-15 mice/group). Likewise, inhibition of Syk, an upstream kinase of Card9, resulted in abrogation of TDB-induced EAU (p<0.05 vs. vehicle control; n=15 mice/group). These results demonstrate that Mincle signaling is both necessary and sufficient to support EAU. BM chimera experiments showed that Card9 expression was required in hematopoietic, rather than non-hematopoietic cells (p<0.05; n=10 mice/group). Since Card9 is primarily expressed by myeloid cells, contribution of DC-specific Syk was investigated. Syk-deficiency in DCs alone resulted in significantly reduced disease in early induction of EAU (p<0.05 vs controls; n=6-10 mice/group).
These studies uncover an essential role for Mincle and the Syk/Card9-coupled signaling axis in autoimmune uveitis. This could provide novel targets for treatment of ocular inflammation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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