title: 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.
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Chang
authors.initials: C
authors.lastname: He
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.affiliation: Immunoregulation Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mattapallil
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Microbiology & Cell Science, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Joseph
authors.identifier: 0000-0003-2066-6814
authors.initials: J
authors.lastname: Larkin Iii
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Charles E
authors.identifier: 0000-0002-9986-3839
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D032701:Biomimetics; D002908:Chronic Disease; D005434:Flow Cytometry; D053614:Janus Kinase 2 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000737:chemistry*; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy*
chemical_list: D010455:Peptides; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; C507927:Jak2 protein, rat; D053614:Janus Kinase 2