RT Journal Article
SR Electronic
T1 IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1900154
DO 10.1183/13993003.00154-2019
A1 A. Gungl
A1 S. Crnkovic
A1 V. Biasin
A1 L.M. Marsh
A1 B. Odler
A1 A. Sahu-Osen
A1 E. Stacher-Priehse
A1 L. Brcic
A1 F. Schneider
A1 N. Cikes
A1 B. Ghanim
A1 W. Klepetko
A1 W. Graninger
A1 Y. Allanore
A1 R. Eferl
A1 A. Olschewski
A1 H. Olschewski
A1 G. Kwapiszewska
YR 2019
UL http://erj.ersjournals.com/content/early/2019/06/26/13993003.00154-2019.abstract
AB The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1β in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1β were localised in lungs of SSc patients' and in the Fra-2 transgenic (TG) mouse model of SSc. Lung function, hemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg−1·day−1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMC) and parenchymal fibroblasts (PF) were investigated in vitro.Fra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. IL-1α and IL-1β immunoreactivity was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMC and PF via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced Th2 inflammation and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Gungl reports grants from Jubilee Foundation of the Austrian National Bank, during the conduct of the study.Conflict of interest: Dr. Crnkovic has nothing to disclose.Conflict of interest: Dr. Biasin has nothing to disclose.Conflict of interest: Dr. Marsh has nothing to disclose.Conflict of interest: Dr. Odler has nothing to disclose.Conflict of interest: Dr. Sahu-Osen has nothing to disclose.Conflict of interest: Dr. Stacher has nothing to disclose.Conflict of interest: Dr. Brcic reports grants and personal fees from Astra Zeneca, personal fees from Roche Austria, non-financial support from MSD Austria, non-financial support from Pfizer Austria, outside the submitted work.Conflict of interest: Dr. Schneider has nothing to disclose.Conflict of interest: Dr. Cikes has nothing to disclose.Conflict of interest: Dr. Ghanim has nothing to disclose.Conflict of interest: Dr. Klepetko has nothing to disclose.Conflict of interest: Dr. Graninger has nothing to disclose.Conflict of interest: Dr. Allanore has nothing to disclose.Conflict of interest: Dr. Eferl has nothing to disclose.Conflict of interest: Dr. Olschewski has nothing to disclose.Conflict of interest: Dr. Olschewski reports personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from MSD, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Novartis, grants from Inventiva, personal fees from Bellerophon, outside the submitted work; and Horst Olschewski is part time employee of Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.Conflict of interest: Dr. Kwapiszewska reports grants from Jubilee Foundation of the Austrian National Bank, grants from Austrian Science Fund (FWF), grants from Austrian agency for international mobility and cooperation in education, science and research, during the conduct of the study.