Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases that includes Behets disease, birdshot retinochoroidopathy, VogtKoyanagiHarada disease, sympathetic ophthalmia, and ocular sarcoidosis. The etiology of uveitis is not fully understood but may be linked to autoimmunity. Cytokine signaling plays critical roles in the pathology of uveitis. IL-17 is substantially elevated in freshly isolated PBMC from patients with active uveitis, as well as in PBMC and lymph nodes of mice with experimental autoimmune uveitis (EAU), a model of human uveitis. The increase in IL-17 upregulates TNF- in the retina, suggesting a mechanism by which Th17 cells contribute to ocular pathology during uveitis. Transcription factors that regulate Th17 development and effector functions also play important roles in pathophysiology of uveitis. Thus, identifying transcription factors that regulate cytokine signaling and Th17 cells has therapeutic potential in the treatment of uveitis. We report the increased secretion of IL-1 in the retina by neutrophils, macrophages, and dendritic cells during ocular inflammation and show that loss of IL-1R signaling confers protection from experimental autoimmune uveitis. Amelioration of experimental autoimmune uveitis in Il1r-deficient mice was associated with reduced infiltration of inflammatory cells into the retina and decreased numbers of uveitogenic Th17 cells that mediate uveitis. We also reveal dual function of the IRF8 transcription factor in pathophysiology of autoimmune uveitis as the loss of IRF8 in T cells exacerbates uveitis, while deletion of Irf8 in the retina confers protection from development of severe uveitis. We further show that sInterferon regulatory factor 8 (IRF-8) as well as suppressor of cytokine signaling 1 (SOCS1) confer protection from ocular pathology during HSV-1 infection by restraining the activation and expansion of T Cells. These findings indicate the possible utility of manipulating levels of IL-1R, SOCS proteins and/or IRF8 for the treatment of ocular inflammatory diseases.
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