Epithelial alarmins: a new target to treat chronic respiratory diseases

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).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.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.