Regulation of JAK/STAT pathways in the eye

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The inflammatory cytokine, IL-23, induces nave T cells to mount immune responses dominated by IL-17 producing T-helper cells (Th17) that have been implicated in the etiology of several human inflammatory diseases, including uveitis and scleritis. IL-23 mediates its biological activities through activation of STAT3 pathways. Recent reports have also indicated that STAT3 is required for commitment of naive T cells towards the Th17 developmental pathway, suggesting involvement of STAT3 pathway in CNS inflammatory diseases. The role of Th17 in etiology of uveitis was recently established in experimental autoimmune uveoretinitis (EAU), a T cell-mediated intraocular inflammatory disease that shares essential immunopathologic features with human uveitis. Mice with targeted deletion of STAT3 in CD4+ T-cells do not develop EAU or experimental autoimmune encephalitis or EAE (mouse model of multiple sclerosis) because of their inability to generate pathogenic Th17 cells. STAT3 is also required for α2β4 integrin activation and T cell trafficking into CNS: inflammatory STAT3-deficient T cells do not enter the eye or brain. STAT3 is therefore an attractive therapeutic target that can be used to inhibit uveitis. This study focuses on therapeutic targeting of STAT3 pathways. Two experimental approaches have been used. (i) In the first set of studies, STAT3 pathways were targeted by using a membrane-penetrating SOCS3 proteins. SOCS3 is a potent endogenous intracellular inhibitor of STAT3 pathways. We have generated a recombinant SOCS3 protein that is fused to a hydrophobic 12 AA sequence of the signal peptide of the Karposi FGF4 protein. This recombinant SOCS3 protein can penetrate the cell membrane and we have used it to inhibit IL-6-induced STAT3 activation in macrophages and T cells. We have also used this protein to inhibit the expansion of polarized Th17 cells in vitro and our next step is to optimize it for use in animal studies of EAU. (ii) A STAT3 inhibitor (NCE) comprised of a small chemical molecule was recently developed by Orchid Research Labs Limited, Chennai, India. NCE is a selective inhibitor of STAT3 and has been effective in pre-clinical models of oncology. Through an MTA agreement between the NEI and Orchid Research Labs we obtained this compound and have evaluated its efficacy against uveitis. Our studies in the experimental autoimmune uveitis model reveal that it inhibits the progression of posterior uveitis. We have also validated these results with other STAT3 inhibitors.