Epithelial alarmins: a new target to treat chronic respiratory diseases

ABSTRACTIntroduction 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 rates 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 offer an interesting option to treat severe asthma and COPD but future investigations are needed to established their place in the treatment strategies.KEYWORDS: Alarminsbiologicschronic respiratory diseasesexacerbationslung functionDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsThe airway and alveolar epithelium acts 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 diseases pathogenesis and to develop adequate therapeutic approaches.Declaration of interestD Nedeva 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.K Kowal 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.A Tiotiu 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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.ER : exacerbation rate ; ACQ : Asthma Control Questionnaire ; AQLQ : Asthma Quality of Life Questionnaire ; FEV1 : forced expiratory volume in 1 second ; AHR : airway hyperresponsivenness ; BEC : blood eosinophils count ; FeNO : fractional exhaled nitric oxide ; IgE : immunoglobulin E ; OCS : oral corticosteroids ; SGRQ : St. George’s Respiratory Questionnaire ; * : former-smokersFigure 1 : Epithelial airway altered structure in asthma, COPD, idiopathic pulmonary fibrosis and cystic fibrosis (adaptation of two previously published figures from [1,Citation6])Display full sizeFigure 2 : Role of thymic stromal lymphopoietin (TSLP) in airway inflammation, remodeling and fibrosisDisplay full sizeDC :dendritic cells ; Th: T-helper cells ; TSLP : thymic stromal lymphopoietin ; IL-33 : interleukin 33 ; IL-25 : interleukin 25 ; M1 : macrophage type 1 ; NE : neutrophil ; TNFα : tumor necrosis factor alpha ; IL-1β : interleukin-1 beta ; IL-6 : interluekin 6 ; CXCL-8 : chemokine (C-X-C motif) ligand 8; GM-CSF : granulocyte-macrophage colony-stimulating factor ; AEC2 : alveolar type 2 epithelial cells ; DAMPs : damage-associated molecular patterns ; ILC2 : type 2 innate lymphoid cells ; IL-4 : interleukin 4 ; IL-13 : interleukin 13 ; TGFβ : transforming growth factor beta ; PDGF : platelet-derived growth factorILC2 : type 2 innate lymphoid cells ; Th : T-helper cells ; ASM : airway smooth muscle cell ; IL-4 : interleukin 4 ; IL-5: interleukin 5 ; IL-13 : interleukin 13 ; IL-9 : interleukin 9 ; IL-17A : interleukin 17AFigure 3 : Role of interleukin 33 (IL-33) in airway inflammation, remodeling and fibrosisDisplay full sizeTh : T-helper cells ; NK : natural killer ; DC : dendritic cells ; ILC2 : type 2 innate lymphoid cells ; TNFα : tumor necrosis factor alpha ; IL-1β : interleukin-1 beta ; IL-6 : interluekin 6 ; IL-13 : interleukin 13 ; IL-8 : interleukin 8 ; IL-4 : interleukin 4 ; IL-5: interleukin 5 ; ASM : airway smooth muscle cellFigure 4 : Role of interleukin 25 (IL-25) in airway inflammation, remodeling and fibrosisDisplay full sizeDC :dendritic cells ; Th : T-helper cells ; ILC2 : type 2 innate lymphoid cells ; ASM : airway smooth muscle cell ; IL-4 : interleukin 4 ; IL-5: interleukin 5 ; IL-9: interleukin 9 ; IL-13 : interleukin 13Additional informationFundingThis paper was not funded.