The Anti-Inflammatory Effect of KS23, A Novel Peptide Derived From Globular Adiponectin, on Endotoxin-Induced Uveitis in Rats.

Xin Shi,Chingyi Wang,Xindan Xing,Junwei Fang,Tian Niu,Shaopin Zhu,Yihan Wang,Kun Liu,Huiyi Jin,Hanying Wang

doi:10.3389/fphar.2020.585446

Abstract

Purpose: Adiponectin has been shown to exert potent anti-inflammatory activities in a range of systemic inflammatory diseases. This study aimed to investigate the potential therapeutic effects of KS23, a globular adiponectin-derived peptide, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated mouse macrophage-like RAW 264.7 cells. Methods: EIU was induced in Lewis rats by subcutaneous injection of LPS into a single footpad. KS23 or phosphate-buffered saline (PBS) was administered immediately after LPS induction via intravitreal injection. Twenty-four hours later, clinical and histopathological scores were evaluated, and the aqueous humor (AqH) was collected to determine the infiltrating cells, protein concentration, and levels of inflammatory cytokines. In vitro, cultured RAW 264.7 cells were stimulated with LPS in the presence or absence of KS23, inflammatory cytokine levels in the supernatant, nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65, and the expression of NF-kB signaling pathway components were analyzed. Results: KS23 treatment significantly ameliorated the clinical and histopathological scores of EIU rats and reduced the levels of infiltration cells, protein, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the aqueous humor. Consistently, KS23 decreased the expression of TNF-α and IL-6 in the supernatant of LPS-stimulated RAW 264.7 cells and inhibited the LPS-induced nuclear translocation of NF-κB p65 and the phosphorylation of IKKα/β/IκBα/NF-κB. Conclusion: The in vivo and in vitro results demonstrated the anti-inflammatory effects of the peptide KS23 and suggested that KS23 is a compelling, novel therapeutic candidate for the treatment of ocular inflammation.

Highlights

Uveitis is a group of intraocular inflammatory diseases involving the uvea, retina, retinal vessels, and vitreous, and it is one of the leading causes of vision loss, accounting for 10–20% of legal blindness every year (Chang and Wakefield, 2002; Durrani et al, 2004; Nguyen et al, 2011)
Our results showed that KS23 prevented ocular inflammatory changes in rats associated with Endotoxin-induced uveitis (EIU) and suppressed the IKKα/β/IκBα/nuclear factor kappa B (NF-κB) signaling pathway in LPS-stimulated RAW 264.7 cells
These findings demonstrate that KS23 could be a potential therapeutic agent for ocular inflammation

Summary

Introduction

Uveitis is a group of intraocular inflammatory diseases involving the uvea, retina, retinal vessels, and vitreous, and it is one of the leading causes of vision loss, accounting for 10–20% of legal blindness every year (Chang and Wakefield, 2002; Durrani et al, 2004; Nguyen et al, 2011). Endotoxin-induced uveitis (EIU) is an experimental model of acute ocular inflammation induced by the topical application of lipopolysaccharide (LPS), which is a constituent of Gramnegative bacterial cell walls, into footpads of rodents (Rosenbaum et al, 1980). This model induces an acute, predominately anterior, uveitis that peaks approximately 24 h after injection (Chang et al, 2008). EIU has been widely accepted as an in vivo model for assessing the pharmacological and immunological effects of drugs on intraocular inflammation (Uchida et al, 2017; Shoeb et al, 2018)

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