BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats.

Jianle Wang,Yan Wu,Yu Chen,Yifei Zhou,Naifeng Tian,Dongdong Lin,Xiaolei Zhang,Weiyang Gao,Yaosen Wu,Ben Wang,Jiaoxiang Chen,Xiangyang Wang,Haiming Jin,Ximiao Chen,Sunli Hu

doi:10.1111/jcmm.14196

Abstract

The pathophysiology of spinal cord injury (SCI) involves primary injury and secondary injury. For the irreversibility of primary injury, therapies of SCI mainly focus on secondary injury, whereas inflammation is considered to be a major target for secondary injury; however the regulation of inflammation in SCI is unclear and targeted therapies are still lacking. In this study, we found that the expression of BRD4 was correlated with pro‐inflammatory cytokines after SCI in rats; in vitro study in microglia showed that BRD4 inhibition either by lentivirus or JQ1 may both suppress the MAPK and NF‐κB signalling pathways, which are the two major signalling pathways involved in inflammatory response in microglia. BRD4 inhibition by JQ1 not only blocked microglial M1 polarization, but also repressed the level of pro‐inflammatory cytokines in microglia in vitro and in vivo. Furthermore, BRD4 inhibition by JQ1 can improve functional recovery and structural disorder as well as reduce neuron loss in SCI rats. Overall, this study illustrates that microglial BRD4 level is increased after SCI and BRD4 inhibition is able to suppress M1 polarization and pro‐inflammatory cytokine production in microglia which ultimately promotes functional recovery after SCI.

Highlights

Traumatic spinal cord injury (SCI) is a devastating neurological condition which involves primary injury and secondary injury.[1-3]
This study provides evidence that Bromodomain‐containing protein 4 (BRD4) plays a critical role in modulating inflammatory response after SCI in rats
We found that (a) pro‐inflammatory cytokines promote the level of BRD4 in microglia after SCI; (b) BRD4 knockdown and JQ1 alleviate activation of signalling pathways of NF‐κB and Mitogen‐activated protein kinases (MAPKs) in LPS‐treated microglia; (c) inhibition of BRD4 by JQ1 compromises the expression of pro‐inflammatory cytokines and M1 polarization in microglia; (d) administration of JQ1 reduces microglial M1 polarization and secretion of pro‐inflammatory cytokines in injured spinal cord; (e) BRD4 inhibition by JQ1 ameliorates secondary damage in spinal cord after SCI in rats

Summary

| INTRODUCTION

Traumatic spinal cord injury (SCI) is a devastating neurological condition which involves primary injury and secondary injury.[1-3]. During development of SCI, M2 polarized microglia are able to remove apoptotic cells and inappropriate neural connections, whereas M1 polarized microglia in the injured spinal cord generate various pro‐inflammatory cytokines, such as TNF‐α, IL‐1β and IL‐6, which aggravate the secondary injury after SCI.[8,9]. The phosphorylation of p38 mitogen‐activated protein kinase (MAPK), c‐Jun N‐terminal kinase (JNK) and extracellular signal regulated kinase (ERK) is markedly increased in microglia, which may lead to increased expression of pro‐inflammatory phenotypes such as TNF‐α, IL‐1β, IL‐6 and INOS.[13,14]. BRD4 inhibition by JQ1 was demonstrated to attenuate LPS‐induced expression of pro‐inflammatory cytokines and suppressed inflammatory reactions in macrophages;[16] studies showed that JQ1 negatively modulates inflammation in rheumatoid arthritis and osteoarthritis indicating that suppression of BRD4 might be a potential therapeutic method against inflammatory response in SCI.[17,18]. This study demonstrated that BRD4 inhibition can attenuate inflammatory response in microglia and BRD4 inhibition by JQ1 could be a potential novel therapy for SCI

| Ethics statement

Findings

| DISCUSSION