CXCL5/CXCR2 modulates inflammation-mediated neural repair after optic nerve injury

Yanxuan Xu,Ling-Ping Cen,Shaofen Huang,Yu-Fen Liu,Shao-Lang Chen,Shaowan Chen,Jia-Jian Liang,Tsz Kin Ng,Xi Zhuang,Mingzhi Zhang,Ciyan Xu,Zhanchi Hu,Chi Pui Pang

doi:10.1016/j.expneurol.2021.113711

Abstract

BackgroundPrevious studies reported that mild inflammation promotes retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury with involvement of infiltrating macrophages and neutrophils. Here we aimed to evaluate the involvement and regulation of the main inflammatory chemokine pathway CXCL5/CXCR2 in the inflammation-mediated RGC survival and axonal regeneration in mice after ON injury. MethodsThe expressions and cellular locations of CXCL5 and CXCR2 were confirmed in mouse retina. Treatment effects of recombinant CXCL5 and CXCR2 antagonist SB225002 were studied in the explant culture and the ON injury model with or without lens injury. The number of RGCs, regenerating axons, and inflammatory cells were determined, and the activation of Akt andSTAT3 signaling pathways were evaluated. ResultsCxcr2 and Cxcl5 expressions were increased after ON and lens injury. Addition of recombinant CXCL5 promoted RGC survival and neurite outgrowth in retinal explant culture with increase in the number of activated microglia, which was inhibited by SB225002 or clodronate liposomes. Recombinant CXCL5 also alleviated RGC death and promoted axonal regeneration in mice after ON injury, and promoted the lens injury-induced RGC protection with increase in the number of activated CD68+ cells. SB225002 inhibited lens injury-induced cell infiltration and activation, and attenuated the promotion effect on RGC survival and axonal regeneration through reduction of lens injury-induced Akt activation. ConclusionsCXCL5 promotes RGC survival and axonal regeneration after ON injury and further enhances RGC protection induced by lens injury with CD68+ cell activation, which is attenuated by CXCR2 antagonist. CXCL5/CXCR2 could be a potential therapeutic target for RGC survival promotion after ON injury.

Highlights

Optic nerve (ON) can be suffered from injury by multiple conditions, including trauma, ischemia, immune disorders, poisoning, tumor and metabolic disorders
chemokine receptor 2 (Cxcr2) and chemokine ligand 5 (Cxcl5) expressions were increased after optic nerve (ON) and lens injury
Addition of recombinant Cxcl5 promoted retinal ganglion cell (RGC) survival and neurite outgrowth in retinal explant culture with increase in the number of activated microglia, which was inhibited by SB225002 or clodronate liposomes

Summary

Introduction

Optic nerve (ON) can be suffered from injury by multiple conditions, including trauma, ischemia, immune disorders, poisoning, tumor and metabolic disorders. About 50% of individuals affected with traumatic optic neuropathy suffer permanent vision loss even after clinical treatments due to progressive degeneration of retinal ganglion cells (RGCs) and their axons [2]. Subsequent studies have identified oncomodulin combined with cyclic adenosine monophosphate (cAMP) elevation, ciliary neurotrophic factor (CNTF), chemokine SDF-1/CXCL12 contributing to this inflammation-mediated neural repair [11,12,13,14]. Previous studies reported that mild inflammation promotes retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury with involvement of infiltrating macrophages and neutrophils. We aimed to evaluate the involvement and regulation of the main inflammatory chemokine pathway Cxcl5/Cxcr in the inflammation-mediated RGC survival and axonal regeneration in mice after ON injury

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