Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

Michelle L Manni,Andres Salmeron,Sivanarayana Mandalapu,John F Alcorn,Jose M Lora,Jay K Kolls

doi:10.1038/srep43139

Abstract

Atopic asthma is a prevalent respiratory disease that is characterized by inflammation, mucus hypersecretion, and airway hyperresponsiveness. The complexity of this heterogeneous disorder has commanded the need to better define asthma phenotypes based on underlying molecular mechanisms of disease. Although classically viewed as a type 2-regulated disease, type 17 helper T (Th17) cells are known to be influential in asthma pathogenesis, predominantly in asthmatics with neutrophilia and severe refractory disease. Bromodomain and extra-terminal domain (BET) chromatin adaptors serve as immunomodulators by directly regulating Th17 responses and Th17-mediated pathology in murine models of autoimmunity and infection. Based on this, we hypothesized that BET proteins may also play an essential role in neutrophil-dominant allergic airway disease. Using a murine model of neutrophil-dominant allergic airway disease, we demonstrate that BET inhibition limits pulmonary inflammation and alters the Th17-related inflammatory milieu in the lungs. In addition, inhibition of BET proteins improved lung function (specifically quasi-static lung compliance and tissue elastance) and reduced mucus production in airways. Overall, these studies show that BET proteins may have a critical role in asthma pathogenesis by altering type 17 inflammation, and thus interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma.

Highlights

Fluid and (C) Bronchoalveolar lavage (BAL) fluid cell differential counts
Previous work has shown that adoptive transfer of OVA-specific Th17 cells into OVA-treated BALB/c SCID mice is sufficient to promote neutrophilic inflammation, AHR, and mucus metaplasia, which are not affected by glucocorticoid treatment[3]
CPI-203 treatment during Th17-driven allergic airway disease attenuated inflammation in the airspaces of the lungs and resulted in significantly lower levels of macrophages, lymphocytes, and neutrophils (Fig. 1B,C). These results suggest that the steroid-insensitive neutrophilia in the airspaces that was induced by Th17-mediated allergic airway disease, was reduced by CPI-203 treatment

Summary

Introduction

Fluid and (C) BAL fluid cell differential counts. Mice in control and CPI-203 groups received all OVA challenges, but phosphate buffered saline retro-orbitally at time of cell transfer. Based on the fundamental role of BET bromodomains in cell growth and proliferation, recent studies have focused on establishing a link between BET proteins and inflammatory responses in disease. Mimics of BET bromodomains have been shown to inhibit airway smooth muscle cell proliferation and cytokine release from patients with asthma[22,23]. Based on these findings and the role of BET proteins in Th17 cell function, we hypothesize that the BET inhibitor CPI-203 would limit asthma pathogenesis in a Th17-induced murine model of severe refractory asthma. This work establishes a role for BET proteins in Th17-mediated allergic airway disease and suggests that interfering with BET-dependent chromatin signaling may provide clinical benefits to patients suffering from asthma

Methods

Results

Conclusion