Fibroblast Growth Factor 22 Inhibits ER Stress-Induced Apoptosis and Improves Recovery of Spinal Cord Injury.

Sipin Zhu,Mengji Chen,Qiuji Wu,Min Chen,Kehe Yu,Jiahui Ye,Yibo Ying,Liyunian Bai,Wenfei Ni,Fangmin Mao,Haicheng Dou

doi:10.3389/fphar.2020.00018

Abstract

Currently, inhibiting or reducing neuronal cell death is the main strategy to improve recovery of spinal cord injury (SCI). Therapies using nerve growth factors to treat SCI mainly focused on reducing the area damaged by postinjury degeneration to promote functional recovery. In this report, we investigated the mechanism of ER (endoplasmic reticulum) stress-induced apoptosis and the protective action of fibroblast growth factor 22 (FGF22) in vivo. Our results demonstrated that ER stress-induced apoptosis plays a significant role in injury of SCI model rats. FGF22 administration promoted recovery and increased neuron survival in the spinal cord lesions of model mice. The protective effect of FGF22 is related to decreased expression of CHOP (C/EBP-homologous protein), GRP78 (glucose-regulated protein 78), caspase-12, X-box binding protein 1 (XBP1), eukaryotic initiation factor 2α (Eif-2α) and Bad which are ER stress-induced apoptosis response proteins. Moreover, FGF22 administration also increased the number of neurons and the expression of growth-associated protein 43 (GAP43) which was related to axon regeneration. We also demonstrated that the protective effect of FGF22 effectively reduces neuronal apoptosis and promotes axonal regeneration. Our study first illustrated that the function of FGF22 is related to the inhibition of ER stress-induced cell death in SCI recovery via activation of downstream signals. This study also suggested a new tendency of FGF22 therapy development in central neural system injuries, which involved chronic ER stress-induced apoptosis.

Highlights

Spinal cord injury (SCI) is a destructive event that usually leads to significant functional impairment for the patient (Angeli et al, 2018)
The unfolded protein response (UPR) activates three signal pathways that are regulated by activating transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), which increases the expression of apoptotic proteins and leads to neuronal death (Lee et al, 2014; Dou et al, 2018)
PC-12 cell lines obtained from the American Type Culture Collection (ATCC) were cultured in RPMI 1640 medium, which consisted of 10% fetal bovine serum (FBS), RPMI 1640 and 1% antibiotics

Summary

Introduction

Spinal cord injury (SCI) is a destructive event that usually leads to significant functional impairment for the patient (Angeli et al, 2018). It triggers very limited regeneration in humans, leading to irreversible damage that can result in permanent motor dysfunction (Kumamaru et al, 2018; Sofroniew, 2018). SCI causes the injury loci to form a hypoxic microenvironment, which in turn causes neuronal death and dysfunction, limiting function recovery after SCI (Sabelstrom et al, 2013). During SCI, a large amount of protein misfolding caused by alteration of the microenvironment in the injured area leads to the unfolded protein response (UPR) (Hetz, 2012). Extensive neuronal death induced by apoptosis is the largest obstacle in recovery of spinal cord injury (Crowe et al, 1997)

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