Endothelin-A Receptor Antagonist Alleviates Allergic Airway Inflammation via the Inhibition of ILC2 Function.

Xiaogang Zhang,Xinyao Li,Zhe Xing,Hengbiao Sun,Xiao Lu,Jingping Liu,Yumei He,Ziyang Chen,Meiqi Chen,Gang Xiao,Shaowen Zuo

doi:10.3389/fimmu.2022.835953

Abstract

Allergic airway inflammation is a universal airway disease that is driven by hyperresponsiveness to inhaled allergens. Group 2 innate lymphoid cells (ILC2s) produce copious amounts of type 2 cytokines, which lead to allergic airway inflammation. Here, we discovered that both peripheral blood of human and mouse lung ILC2s express the endothelin-A receptor (ETAR), and the expression level of ETAR was dramatically induced upon interleukin-33 (IL-33) treatment. Subsequently, both preventive and therapeutic effects of BQ123, an ETAR antagonist, on allergic airway inflammation were observed, which were associated with decreased proliferation and type 2 cytokine productions by ILC2s. Furthermore, ILC2s from BQ123 treatment were found to be functionally impaired in response to an interleukin IL-33 challenged. And BQ123 treatment also affected the phosphorylation level of the extracellular signal-regulated kinase (ERK), as well as the level of GATA binding protein 3 (GATA3) in activated ILC2s. Interestingly, after BQ123 treatment, both mouse and human ILC2s in vitro exhibited decreased function and downregulation of ERK signaling and GATA3 stability. These observations imply that ETAR is an important regulator of ILC2 function and may be involved in ILC2-driven pulmonary inflammation. Therefore, blocking ETAR may be a promising therapeutic strategy for allergic airway inflammation.

Highlights

Hyperresponsive allergic inflammation is one of the most common chronic respiratory diseases worldwide and has been the most frequently diagnosed chronic disease among children in the past decade [1–5]
We elucidated the mechanism of action, signaling pathways, and therapeutic potential of BQ123, an endothelin-A receptor (ETAR) antagonist, using pulmonary ILC2s in the context of lung inflammation
The expression of ETAR by ILC2s during pulmonary inflammation implies the therapeutic viability of targeting ETAR

Summary

Introduction

Hyperresponsive allergic inflammation is one of the most common chronic respiratory diseases worldwide and has been the most frequently diagnosed chronic disease among children in the past decade [1–5]. Allergic inflammation is often defined as a reversible airway obstruction, which can lead to immunological imbalance, inflammation of the airway mucosa, and eventually. ETAR Antagonist Alleviates Airway Inflammation irreversible lung function impairment [6]. The majority of patients exhibit an overexpression of genes involved in type 2 inflammatory pathways [7–10]. Emerging evidence suggests that type 2 inflammation mainly involves the infiltration of lymphocytes, especially eosinophils, into the lung [8–11]. Patients show a poor quality of life and a high risk of mortality [1, 2]. Understanding the underlying cellular and molecular mechanisms of pathogenesis could lay a theoretical foundation for developing novel therapeutic strategies for allergic airway inflammation

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Results

Conclusion