SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis)

Abstract

Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU. To further investigate mechanisms that mediate SOCS1-KIR effects and evaluate the efficacy of SOCS1-KIR as an investigational drug for chronic uveitis, we induced EAU in rats by adoptive transfer of uveitogenic T-cells and monitored disease progression and severity by slit-lamp microscopy, histology, and optical coherence tomography. Topical administration of SOCS1-KIR ameliorated acute and chronic posterior uveitis by inhibiting Th17 cells and the recruitment of inflammatory cells into retina while promoting expansion of IL-10-producing Tregs. We further show that SOCS1-KIR conferred protection of resident retinal cells that play critical role in vision from cytotoxic effects of inflammatory cytokines by downregulating proapoptotic genes. Thus, SOCS1-KIR suppresses uveitis and confers neuroprotective effects and might be exploited as a noninvasive treatment for chronic uveitis.

Activation of liver X receptor delayed the retinal degeneration of rd1 mice through modulation of the immunological function of glia

“…The JAK-STAT pathway has been demonstrated to mediate the protection of photoreceptors in rd1 mice [ 33 ] or light-induced retinal degeneration [ 34 ] and be involved in the GFAP expression of Müller cells [ 35 ] in the mouse model. The JAK-STAT pathway can mediate the inhibition of inflammation during mouse uveitis [ 36 , 37 ] and is involved in the inflammatory response in the human AMD eye [ 38 ], suggesting that the JAK-STAT pathway plays an important role in visual inflammation. Additionally, STAT signaling plays a central role during retinal degeneration in the rd10 mouse model [ 39 ].…”

A C-terminal peptide from type I interferon protects the retina in a mouse model of autoimmune uveitis

“…We have shown previously that a R9-conjugated peptide from SOCS1 kinase inhibitor region (R9-SOCS1-KIR), used topically was effective in protecting against EAU, both prophylactically and therapeutically [31]. Palmitoyl-lysine conjugated SOCS1-KIR was reported by others as effective in preventing EAU [71,72]. Eye drop formulations of other CPPs, vascular endothelial growth inhibitor (VEGI) [73], pigment epithelium derived factor peptide (PEDF) peptide [74,75], and endostatin [76] have been reported.…”

A Cell Penetrating Peptide from SOCS-1 Prevents Ocular Damage in Experimental Autoimmune Uveitis

“…Lewis rats (He et al, 2016) in protection against EAU. The R9-attached peptide is thus an improvement over the lipo-mimetic (Jager et al, 2011) for use of KIR peptide.…”