PMID- 36949463 OWN - NLM STAT- MEDLINE DCOM- 20230401 LR - 20230401 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 24 IP - 1 DP - 2023 Mar 23 TI - The IL-33:ST2 axis is unlikely to play a central fibrogenic role in idiopathic pulmonary fibrosis. PG - 89 LID - 10.1186/s12931-023-02334-4 [doi] LID - 89 AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with limited treatment options. Interleukin-33 (IL-33) is proposed to play a role in the development of IPF however the exclusive use of prophylactic dosing regimens means that the therapeutic benefit of targeting this cytokine in IPF is unclear. METHODS: IL-33 expression was assessed in ILD lung sections and human lung fibroblasts (HLFs) by immunohistochemistry and gene/protein expression and responses of HLFs to IL-33 stimulation measured by qPCR. In vivo, the fibrotic potential of IL-33:ST2 signalling was assessed using a murine model of bleomycin (BLM)-induced pulmonary fibrosis and therapeutic dosing with an ST2-Fc fusion protein. Lung and bronchoalveolar lavage fluid were collected for measurement of inflammatory and fibrotic endpoints. Human precision-cut lung slices (PCLS) were stimulated with transforming growth factor-beta (TGFbeta) or IL-33 and fibrotic readouts assessed. RESULTS: IL-33 was expressed by fibrotic fibroblasts in situ and was increased by TGFbeta treatment in vitro. IL-33 treatment of HLFs did not induce IL6, CXCL8, ACTA2 and COL1A1 mRNA expression with these cells found to lack the IL-33 receptor ST2. Similarly, IL-33 stimulation had no effect on ACTA2, COL1A1, FN1 and fibronectin expression by PCLS. Despite having effects on inflammation suggestive of target engagement, therapeutic dosing with the ST2-Fc fusion protein failed to reduce BLM-induced fibrosis measured by hydroxyproline content or Ashcroft score. CONCLUSIONS: Together these findings suggest the IL-33:ST2 axis does not play a central fibrogenic role in the lungs with therapeutic blockade of this pathway unlikely to surpass the current standard of care for IPF. CI - (c) 2023. The Author(s). FAU - Stephenson, Katherine E AU - Stephenson KE AUID- ORCID: 0000-0002-4737-7492 AD - Division of Respiratory Medicine, School of Medicine, University of Nottingham, Nottingham, UK. katherine.stephenson@astrazeneca.com. AD - Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. katherine.stephenson@astrazeneca.com. FAU - Porte, Joanne AU - Porte J AD - Division of Respiratory Medicine, School of Medicine, University of Nottingham, Nottingham, UK. FAU - Kelly, Aoife AU - Kelly A AD - Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. FAU - Wallace, William A AU - Wallace WA AD - Division of Pathology, University of Edinburgh, Edinburgh, UK. FAU - Huntington, Catherine E AU - Huntington CE AD - Biologics Engineering, R&D, AstraZeneca, Cambridge, UK. FAU - Overed-Sayer, Catherine L AU - Overed-Sayer CL AD - Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. FAU - Cohen, E Suzanne AU - Cohen ES AD - Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. FAU - Jenkins, R Gisli AU - Jenkins RG AD - National Heart and Lung Institute, Imperial College London, London, UK. AD - Margaret Turner Warwick Centre for Fibrosing Lung Disease, Imperial College London, London, UK. AD - Interstitial lung disease unit, Royal Brompton Hospital, London, UK. FAU - John, Alison E AU - John AE AD - Division of Respiratory Medicine, School of Medicine, University of Nottingham, Nottingham, UK. AD - National Heart and Lung Institute, Imperial College London, London, UK. AD - Margaret Turner Warwick Centre for Fibrosing Lung Disease, Imperial College London, London, UK. LA - eng GR - MR/N019253/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20230323 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 11056-06-7 (Bleomycin) RN - 0 (Interleukin-1 Receptor-Like 1 Protein) RN - 0 (Interleukin-33) RN - 0 (Transforming Growth Factor beta) RN - 0 (IL33 protein, human) RN - 0 (Il33 protein, mouse) RN - 0 (IL1RL1 protein, human) RN - 0 (Il1rl1 protein, mouse) SB - IM MH - Animals MH - Humans MH - Mice MH - Bleomycin/toxicity MH - Fibroblasts/metabolism MH - *Idiopathic Pulmonary Fibrosis/chemically induced/drug therapy/metabolism MH - Interleukin-1 Receptor-Like 1 Protein/genetics MH - *Interleukin-33/metabolism MH - Lung/metabolism MH - Mice, Inbred C57BL MH - Transforming Growth Factor beta/metabolism PMC - PMC10035257 OTO - NOTNLM OT - Bleomycin-induced pulmonary fibrosis OT - Fibroblasts OT - IL-33 OT - Idiopathic pulmonary fibrosis OT - Precision-cut lung slices OT - ST2 COIS- AstraZeneca partially funded this study and participated in the study design, data collection, data analysis and data interpretation. K.E.S, AK, C.E.H, C.L.O and E.S.C, are employees of AstraZeneca and hold stock or stock options. R.G.J has received grants, contracts or consultancy fees from AstraZeneca, Biogen, Galecto, GlaxoSmithKline, RedX, Pliant, Genetech, Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, Boehringer Ingelheim, Chiesi, Roche, patientMpower, Galapagos and Vicore and has non-financial advisory and leadership roles for NuMedii and Action for Pulmonary Fibrosis respectively. The remaining authors declare no competing interests. EDAT- 2023/03/24 06:00 MHDA- 2023/03/25 06:00 PMCR- 2023/03/23 CRDT- 2023/03/23 00:34 PHST- 2022/10/14 00:00 [received] PHST- 2023/01/18 00:00 [accepted] PHST- 2023/03/23 00:34 [entrez] PHST- 2023/03/24 06:00 [pubmed] PHST- 2023/03/25 06:00 [medline] PHST- 2023/03/23 00:00 [pmc-release] AID - 10.1186/s12931-023-02334-4 [pii] AID - 2334 [pii] AID - 10.1186/s12931-023-02334-4 [doi] PST - epublish SO - Respir Res. 2023 Mar 23;24(1):89. doi: 10.1186/s12931-023-02334-4.