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

Chulbul M Ahmed,Alfred S Lewin,Cristhian J Ildefonso,Howard M Johnson,Anand Swaroop

doi:10.1371/journal.pone.0227524

Chulbul M Ahmed, Alfred S Lewin + Show 3 more

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https://doi.org/10.1371/journal.pone.0227524

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Journal: PloS one	Publication Date: Feb 26, 2020
Citations: 5	License type: CC BY 4.0

Affiliation: University of Florida

Abstract

Experimental autoimmune uveitis (EAU) in rodents recapitulates many features of the disease in humans and has served as a useful tool for the development of therapeutics. A peptide from C-terminus of interferon α1, conjugated to palmitoyl-lysine for cell penetration, denoted as IFNα-C, was tested for its anti-inflammatory properties in ARPE-19 cells, followed by testing in a mouse model of EAU. Treatment with IFNα-C and evaluation by RT-qPCR showed the induction of anti-inflammatory cytokines and chemokine. Inflammatory markers induced by treatment with TNFα were suppressed when IFNα-C was simultaneously present. TNF-α mediated induction of NF-κB and signaling by IL-17A were attenuated by IFNα-C. Differentiated ARPE-19 cells were treated with TNFα in the presence or absence IFNα-C and analyzed by immmunhistochemistry. IFNα-C protected against the disruption integrity of tight junction proteins. Similarly, loss of transepithelial resistance caused by TNFα was prevented by IFNα-C. B10.RIII mice were immunized with a peptide from interphotoreceptor binding protein (IRBP) and treated by gavage with IFNα-C. Development of uveitis was monitored by histology, fundoscopy, SD-OCT, and ERG. Treatment with IFNα-C prevented uveitis in mice immunized with the IRBP peptide. Splenocytes isolated from mice with ongoing EAU exhibited antigen-specific T cell proliferation that was inhibited in the presence of IFNα-C. IFNα-C peptide exhibits anti-inflammatory properties and protects mice against damage to retinal structure and function suggesting that it has therapeutic potential for the treatment of autoimmune uveitis.

Highlights

Uveitis refers to an inflammation affecting the uveal and retinal layers of the eye that accounts for 10–15% of blindness in US[1]
In a series of experiments carried out over twenty years, we have demonstrated for both type I and type II IFNs that the N-terminus of the ligand interacts with the extracellular domain of its cognate receptor and determines the species specificity of IFN action, while the C terminus, after endocytosis, binds to the intracellular domain of the receptor and initiates JAK/STAT signaling similar to the parent IFN
Since enhanced levels of Tumor necrosis factor α (TNFα) have been noted in uveitis patients, we have demonstrated that IFNα-C counteracts the effect of TNFα by down-regulating the cytokines and chemokines that are induced by TNFα (Table 3)

Summary

Introduction

Uveitis refers to an inflammation affecting the uveal and retinal layers of the eye that accounts for 10–15% of blindness in US[1]. In rodent models of the disease, histological analysis shows injury to retinal layers, retinal folds, subretinal fluid, damage to retinal blood vessels and the retinal pigment epithelium (RPE), and choroiditis. Uveitis may affect both the anterior and posterior chambers of the eye [2,3]. Uveitis can arise from an infection, systemic inflammation, or from a local autoimmune response. It may be a component of a systemic

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