title: Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis.
abstract: Uveitis is a diverse group of potentially sight-threatening intraocular inflammatory diseases and pathology derives from sustained production of pro-inflammatory cytokines in the optical axis. Although topical or systemic steroids are effective therapies, their adverse effects preclude prolonged usage and are impetus for seeking alternative immunosuppressive agents, particularly for patients with refractory uveitis. In this study, we synthesized a 16 amino acid membrane-penetrating lipophilic suppressor of cytokine signaling 1 peptide (SOCS1-KIR) that inhibits JAK/STAT signaling pathways and show that it suppresses and ameliorates experimental autoimmune uveitis (EAU), the mouse model of human uveitis. Fundus images, histological and optical coherence tomography analysis of eyes showed significant suppression of clinical disease, with average clinical score of 0.5 compared to 2.0 observed in control mice treated with scrambled peptide. We further show that SOCS1-KIR conferred protection from ocular pathology by inhibiting the expansion of pathogenic Th17 cells and inhibiting trafficking of inflammatory cells into the neuroretina during EAU. Dark-adapted scotopic and photopic electroretinograms further reveal that SOCS1-KIR prevented decrement of retinal function, underscoring potential neuroprotective effects of SOCS1-KIR in uveitis. Importantly, SOCS1-KIR is non-toxic, suggesting that topical administration of SOCS1-Mimetics can be exploited as a non-invasive treatment for uveitis and for limiting cytokine-mediated pathology in other ocular inflammatory diseases including scleritis.
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: He
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, USA.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, USA.
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Mahdi
authors.affiliation: Department of Microbiology & Cell Science, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, USA. Electronic address: egwuaguc@nei.nih.gov.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005451:Fluorescein Angiography; D007109:Immunity; D051379:Mice; D010455:Peptides / Q000008:administration & dosage*; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010455:Peptides; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: Biologics; Experimental autoimmune uveitis (EAU); Ocular inflammation; SOCS1; SOCS1 mimetic; Suppressor of cytokine signaling; Uveitis