Mincle activation and the Syk/Card9 signaling axis are central to the development of autoimmune disease of the eye

Lee, Ellen J., Brown, Brieanna R., Vance, Emily E., Snow, Paige E., Silver, Phyllis B., Heinrichs, David, Lin, Xin, Iwakura, Yoichiro, Wells, Christine A., Caspi, Rachel R. and Rosenzweig, Holly L. (2016) Mincle activation and the Syk/Card9 signaling axis are central to the development of autoimmune disease of the eye. Journal of Immunology, 196 7: 3148-3158. doi:10.4049/jimmunol.1502355

Author Lee, Ellen J.
Brown, Brieanna R.
Vance, Emily E.
Snow, Paige E.
Silver, Phyllis B.
Heinrichs, David
Lin, Xin
Iwakura, Yoichiro
Wells, Christine A.
Caspi, Rachel R.
Rosenzweig, Holly L.
Title Mincle activation and the Syk/Card9 signaling axis are central to the development of autoimmune disease of the eye
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2016-04-01
Year available 2016
Sub-type Article (original research)
DOI 10.4049/jimmunol.1502355
Open Access Status Not Open Access
Volume 196
Issue 7
Start page 3148
End page 3158
Total pages 11
Place of publication Bethesda, MD United States
Publisher American Association of Immunologists
Collection year 2017
Language eng
Formatted abstract
Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA. EAU manifests as posterior ocular inflammation consisting of vasculitis, granulomas, retinal damage, and invasion of self-reactive T cells, which are key clinical features of human uveitis. Our studies uncover Card9 as a critical genetic determinant for EAU. Card9 was responsible for Th17 polarization and Th17-associated Ag-specific responses, but not Th1-associated responses. Nonetheless, Card9 expression was essential for accumulation of both lineages within the eye. Consistent with its recently identified role as an intracellular signaling mediator for C-type lectin receptors (CLRs), a Card9-dependent transcriptional response in the neuroretina was observed involving genes encoding the CLRs Dectin-1, Dectin-2, and Mincle. Genetic deletion of these individual CLRs revealed an essential role for Mincle. Mincle activation was sufficient to generate the EAU phenotype, and this required activation of both Syk and Card9. In contrast, Dectin-1 contributed minimally and a possible repressive role was shown for Dectin-2. These findings extend our understanding of CLRs in autoimmune uveitis. The newly identified role of Mincle and Syk/Card9-coupled signaling axis in autoimmune uveitis could provide novel targets for treatment of patients with ocular inflammatory disease.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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