JQ1 as a BRD4 Inhibitor Blocks Inflammatory Pyroptosis-Related Acute Colon Injury Induced by LPS.

Ling Chen,Menglin Li,Xiaolin Zhong,Mengmeng Shi,Yincheng Deng,Xuyu Zu,Jianghua Liu,Wei Li,Mingli Mao,Yuan Zhang,Hui Yang,Wenyu Cao

doi:10.3389/fimmu.2021.609319

Abstract

Endotoxemia is a severe inflammation response induced by infection especially bacterial endotoxin translocation, which severely increases mortality in combination with acute colon injury. Bromodomain-containing protein 4 (BRD4) is an important Bromo and Extra-Terminal (BET) protein to participate in inflammatory responses. However, it is still unknown about the specific connection between BRD4 and inflammation-related pyroptosis in endotoxemia colon. Here, through evaluating the mucous morphology and the expression of tight junction proteins such as occludin and ZO1, we found the upregulation of BRD4 in damaged colon with poor tight junction in an endotoxemia mouse model induced by lipopolysaccharides (LPS). Firstly, the BRD4 inhibitor JQ1 was used to effectively protect colon tight junction in endotoxemia. As detected, high levels of pro-inflammation cytokines IL6, IL1β and IL18 in endotoxemia colon were reversed by JQ1 pretreatment. In addition, JQ1 injection reduced endotoxemia-induced elevation of the phosphorylated NF κB and NLRP3/ASC/caspase 1 inflammasome complex in colon injury. Furthermore, activated pyroptosis markers gasdermins in endotoxemia colon were also blocked by JQ1 pretreatment. Together, our data indicate that BRD4 plays a critical role in regulating pyroptosis-related colon injury induced by LPS, and JQ1 as a BRD4 inhibitors can effectively protect colon from endotoxemia-induced inflammation injury.

Highlights

Bacterial endotoxin translocation from gastrointestinal tract to the systemic circulation to cause endotoxemia [1]
Lower protein levels of occludin and ZO1 in endotoxemia colons compared to the saline-treated control were detected by western blot (Figure 1B)
We discovered the rising gene and protein expression of an inflammasome complex containing NLRP3, associated speck-like protein (ASC), and cleaved caspase 1 in endotoxemia colons compared to the control ones, which was decreased by Bromodomain-containing protein 4 (BRD4) inhibition (Figures 4B, C)

Summary

Introduction

Bacterial endotoxin translocation from gastrointestinal tract to the systemic circulation to cause endotoxemia [1]. As an acute infection-related inflammatory response, endotoxemia is reported to exacerbate atherosclerosis, steatosis, insulin resistance, and atherosclerosis, and to cause various biological and clinical effects in the host [1, 2]. Lipopolysaccharides (LPS) is a typical bacterial endotoxin to extensively applied in bacterial endotoxemia mice model [3]. Most endotoxemia-related gut disease study is mainly focused on the intestine, especially jejunal [4,5,6]. Compared with endotoxemia-related intestine injury, there are relatively less study on endotoxemia-induced colon injury, which is a common complication of endotoxemia. Colon plays a key role in human immune system with distinct microbial and immune niches [7].

Methods

Results

Conclusion