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Pharmacological Modulation of BET Family in Sepsis

Nian Wang, Runliu Wu, Paul B. Comish, Rui Kang * and Daolin Tang *

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host’s uncontrolled response to infection.

The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production.

Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II.

Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.

Keywords: bromodomain and extra-terminal, inhibitor, innate immune, inflammation, sepsis

INTRODUCTION

Sepsis is a medical condition driven by an unrestricted host response to infection and subsequent multiple organ dysfunction or failure (Singer et al., 2016).

While bacterial infections are considered to be the most common causes of sepsis, other pathogen infections, such as fungus, virus, and parasite, also initiate sepsis (Dolin et al., 2019).

Despite considerable medical advances in recent years, especially intensive care support and the application of antibiotics, the mortality rate of patients with sepsis remains high (>25%).

Once patients develop septic shock with multiple organ dysfunction syndrome (MODS), the mortality rate can reach as high as 70% (Rudd et al., 2020).

Thus, sepsis is still a big challenge in modern medicine.

The pathophysiology of sepsis is complex and involves multiple steps (Kang et al., 2018; Chen et al., 2019).

Cytokine storm, a well-established mechanism for sepsis, results in uncontrolled inflammatory responses (Chousterman et al., 2017).

However, antibody drugs targeting cytokines (e.g., tumor necrosis factor [TNF] and interleukin 6 [IL6]), inflammatory pathways (e.g., toll like receptor 4 [TLR4]), or endotoxin, as well as empiric antibiotic therapies have little or disappointing benefit for patients with sepsis (Chaudhry et al., 2013).

Since the production of inflammation and immune response genes involved in sepsis is strictly controlled at the transcriptional, posttranscriptional, translational, and posttranslational levels, targeting these regulatory pathways may reasonably provide potential treatment strategies for sepsis (Carson et al., 2011; Vachharajani and McCall, 2019).

Edited by:

Abdur Rauf,

University of Swabi, Pakistan

Reviewed by:

Md. Sahab Uddin,

Southeast University, Bangladesh

Olesya Kharenko,

Zenith Epigenetics Ltd., Canada

*Correspondence:

Rui Kang

rui.kang@utsouthwestern.edu

Daolin Tang

daolin.tang@utsouthwestern.edu

Specialty section:

This article was submitted to

Experimental Pharmacology and Drug

Discovery, a section of the journal

Frontiers in Pharmacology

Received: 15 December 2020

Accepted: 25 January 2021

Published: 11 March 2021

Citation:

Wang N, Wu R, Comish PB, Kang R

and Tang D (2021) Pharmacological

Modulation of BET Family in Sepsis.

Front. Pharmacol. 12:642294.

doi: 10.3389/fphar.2021.642294

Frontiers in Pharmacology | www.frontiersin.org 1 March 2021 | Volume 12 | Article