Regulation of JAK/STAT pathways in the eye

National Eye Institute

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Abstract

Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases that includes Behcets disease, birdshot retino-choroidopathy, Vogt-Koyanagi-Harada disease, sympathetic ophthalmia, and ocular sarcoidosis. The etiology of uveitis is not fully understood but may be linked to autoimmunity. We previously identified the critical role of STAT3 transcription factor in regulating the development of Th17 cells that mediate uveitis and targeted deletion of STAT3 suppressed uveitis in mice. However, the role of STAT3 in B cells or pathogenic mechanisms of uveitis is not well understood. In this study, we generated mice lacking STAT3 in CD19+ B cells (CD19-STAT3KO) and investigated intrinsic and extrinsic functions of STAT3 in B cells and its potential role in resistance or pathogenesis of organ-specific autoimmune diseases such as uveitis. We show that STAT3 regulates metabolic mechanisms in B cells with significant implications for bioenergetic and metabolic pathways that control cellular homeostasis in B cells. We also found that the CD19-STAT3KO mice develop severe experimental autoimmune uveitis (EAU), an animal model of human uveitis. Exacerbated uveitis in CD19-STAT3KO mice derived in part from enhanced expression of costimulatory molecules on B cells, marked increase of Th17 responses and increased recruitment of granulocytes into the neuroretina. The enhanced autoimmunity upon deletion of STAT3 in B cells is also recapitulated in experimental autoimmune encephalitis, a mouse model of multiple sclerosis. This result thus support our conclusion that STAT3 deletion in B cells enhances inflammation and the effects observed are not model specific. Taken together, STAT3 appear to exert diametrically opposite effects in lymphocytes, with loss of STAT3 in B cells exacerbating uveitis whereas Stat3 deletion in T cells confers protection.