Purchase this article with an account.
Ellen J Lee, Brieanna Brown, Emily Vance, Riley Hazard, Phyllis Silver, Rachel R Caspi, Holly Lallman Rosenzweig; Identification of the vital role of the innate receptor Mincle in the pathogenesis of autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):879.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
We previously demonstrated a role for the Syk/CARD9 signaling axis, a pathway for innate C-type lectin receptors (CLRs), in the pathogenesis of autoimmune uveitis as modeled in experimental autoimmune uveitis, EAU. Here, we investigated further the source and timing of Syk/CARD9-associated disease susceptibility, and delineated the role of individual upstream CLRs (e.g. Dectin-1, Dectin-2, Mincle), which are involved in fungal and/or mycobacterial host defense responses.
EAU was induced by immunization with interphotoreceptor retinoid-binding protein (IRBP) and uveitis was evaluated longitudinally by fundus imaging (TEFI) and histology. The impact of the Syk inhibitor, piceatannol, versus vehicle control, on the effector phase of disease was evaluated in wild-type (WT) mice by initiating treatment (n=10 mice/treatment) after uveitis onset (5mg/kg given on d14,17,21,24 post-immunization) and compared to prophylactic administration of piceatannol (d0,4, 8,12,16) to target the induction phase. To assess the contribution of individual CLRs, onset and severity of uveitis were evaluated in mice deficient in Dectin-1, Dectin-2, or Mincle versus C57BL/6J controls (n=10-20 mice/genotype). Flow cytometry was used to evaluate the composition of ocular leukocytes.
While protection of CARD9 KO mice to EAU was reproduced in WT mice by prophylactic inhibition of the upstream kinase Syk, indicating a role for CARD9 in the disease induction phase, piceatannol did not offer sustained protection when administered therapeutically. By d21 post-immunization, Dectin-1 and Dectin-2 KO mice exhibited similar or exacerbated uveitis compared to WT controls, while Mincle KO mice had significantly reduced uveitis (TEFI p=0.0017, histology p=0.0001). Interestingly, Dectin-1 and Dectin-2 KO mice had increased numbers of leukocytes (particularly macrophages, neutrophils, and CD4+ T cells) compared to WT, while Mincle KO mice had similar composition but few numbers compared to WT.
Syk inhibition studies support a role for the Syk/CARD9 pathway in the induction rather than effector phase of disease. The proximal CLR Mincle, but not Dectin-1 or Dectin-2, is implicated in the initiation of this innate pathway for autoimmune disease in the eye. These findings provide insight into the role of CLRs and the Syk/CARD9 signaling pathway in ocular inflammatory disease.
This PDF is available to Subscribers Only