Epithelial alarmins: a new target to treat chronic respiratory diseases

ABSTRACT

Introduction

In response to injury, epithelial cells release alarmins including thymic stromal lymphopoietin (TSLP), high mobility group-box-1 (HMGB1), interleukin (IL)-33 and −25 that can initiate innate immune responses. These alarmins are recognized as activators of T2-immune responses characteristic for asthma, but recent evidence highlighted their role in non-T2 inflammation, airway remodeling, and pulmonary fibrosis making them an attractive therapeutic target for chronic respiratory diseases (CRD).

Areas covered

In this review, firstly we discuss the role of TSLP, IL-33, IL-25, and HMGB1 in the pathogenesis of asthma, COPD, idiopathic pulmonary fibrosis, and cystic fibrosis according to the published data. In the second part, we summarize the current evidence concerning the efficacy of the antialarmin therapies in CRD. Recent clinical trials showed that anti-TSLP and IL-33/R antibodies can improve severe asthma outcomes. Blocking the IL-33-mediated pathway decreased the exacerbation rate in COPD patients with more important benefit for former-smokers.

Expert opinion

Despite progress in the understanding of the alarmins’ role in the pathogenesis of CRD, all their mechanisms of action are not yet identified. Blocking IL-33 and TSLP pathways offers an interesting option to treat severe asthma and COPD, but future investigations are needed to establish their place in the treatment strategies.

KEYWORDS:

• Alarmins
• biologics
• chronic respiratory diseases
• exacerbations
• lung function

Article highlights

• The airway and alveolar epithelium act as the first line of defense for the lungs against many environmental triggers.

• In response to injuries, the epithelial cells release the alarmins which are important mediators of inflammation.

• Dysfunctional epithelium and persistent inflammation are the key points in the pathogenesis of many chronic respiratory diseases.

• Current evidence showed important contribution of the epithelial alarmins in the pathogenesis of asthma, COPD, IPF, and CF.

• Targeting the epithelial alarmins and their receptors by biotherapies showed benefits for the severe asthma patients and selected patients with COPD.

• Further investigation is needed to clarify all the mechanisms involving the epithelial alarmins in chronic respiratory disease pathogenesis and to develop adequate therapeutic approaches.

Declaration of interest

SM, GGF, PS, HJCN have no conflict of interest.DN reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Berlin Chemie, Takeda, Chiesi, Sanofi ; support for attending meetings and/or travel from Chiesi, Astra Zeneca.

KK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from ALK Abello, Astra Zeneca, Chiesi, Stallergenes, and support for attending meetings and/or travel from Berlin Chemie.

AT reports honoraria for lectures, presentations, speakers bureaus, educational events from ALK, AstraZeneca, Chiesi, GSK, Novartis, Sanofi ; support for attending meetings and/or travel from AstraZeneca, Sanofi ; participation on Advisory Board for Sanofi.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Authors' contributions

All the authors contributed in the writing of the paper, read and approved the manuscript.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.