RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD

Hannelore P Van Eeckhoutte¹, Chantal Donovan^{2

3}, Richard Y Kim^{2

3}, Thomas M Conlon⁴, Meshal Ansari^{4

5}, Haroon Khan⁶, Ranjith Jayaraman⁶, Nicole G Hansbro^{2

6}, Yves Dondelinger⁷, Tom Delanghe⁷, Allison M Beal⁸, Brad Geddes⁹, John Bertin¹⁰, Tom Vanden Berghe^{7

11}, Joyceline De Volder¹, Tania Maes¹, Peter Vandenabeele⁷, Bart M Vanaudenaerde¹², Dieter Deforce¹³, Sonja Škevin^{13

14}, Filip Van Nieuwerburgh^{13

14}, Fien M Verhamme¹, Guy F Joos¹, Sobia Idrees^{2

6}, Herbert B Schiller⁴, Ali Önder Yildirim⁴, Alen Faiz^{2

6}, Mathieu J M Bertrand⁷, Guy G Brusselle¹, Philip M Hansbro^{2

3

6

15}, Ken R Bracke^{16

15}

Affiliations

¹ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.
² School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
³ Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
⁴ Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
⁵ Institute of Computational Biology, Helmholtz Munich, Munich, Germany.
⁶ Centre for Inflammation, Centenary Institute and School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
⁷ VIB-UGent Center for Inflammation Research, Department for Biomedical Molecular Biology, Cell Death and Inflammation Unit, Ghent University, Ghent, Belgium.
⁸ Immunology Research Unit, GlaxoSmithKline, Collegeville, PA, USA.
⁹ Research, Prime Medicine Inc., Cambridge, MA, USA.
¹⁰ Immunology and Inflammation Research Therapeutic Area, Sanofi, Cambridge, MA, USA.
¹¹ Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
¹² BREATHE, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
¹³ NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁴ Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁵ These authors contributed equally to this work.
¹⁶ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium ken.bracke@UGent.be.

PMID: 36549711
DOI: 10.1183/13993003.01506-2022

RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD

Hannelore P Van Eeckhoutte et al. Eur Respir J. 2023.

. 2023 Apr 1;61(4):2201506.

doi: 10.1183/13993003.01506-2022. Print 2023 Apr.

Authors

Affiliations

¹ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.
² School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
³ Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
⁴ Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
⁵ Institute of Computational Biology, Helmholtz Munich, Munich, Germany.
⁶ Centre for Inflammation, Centenary Institute and School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia.
⁷ VIB-UGent Center for Inflammation Research, Department for Biomedical Molecular Biology, Cell Death and Inflammation Unit, Ghent University, Ghent, Belgium.
⁸ Immunology Research Unit, GlaxoSmithKline, Collegeville, PA, USA.
⁹ Research, Prime Medicine Inc., Cambridge, MA, USA.
¹⁰ Immunology and Inflammation Research Therapeutic Area, Sanofi, Cambridge, MA, USA.
¹¹ Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
¹² BREATHE, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
¹³ NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁴ Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
¹⁵ These authors contributed equally to this work.
¹⁶ Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium ken.bracke@UGent.be.

PMID: 36549711
DOI: 10.1183/13993003.01506-2022

Abstract

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.

Methods: We assessed RIPK1 expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 ^S25D/S25D kinase-deficient mice and the RIPK1 kinase inhibitor GSK'547.

Results: RIPK1 expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.

Conclusions: RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.

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Conflict of interest statement

Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The RIPK1 kinase inhibitor GSK′547 was a kind gift from A.M. Beal (GlaxoSmithKline) who approved the manuscript but was not involved in funding or designing the study. T. Maes reports grants from FWO Flanders, Chiesi and GlaxoSmithKline, and is a shareholder of Oryzon Genomics and Mendelion Lifesciences SL, outside the submitted work. G.F. Joos reports consulting fees from GlaxoSmithKline and AstraZeneca, lecture honoraria from GlaxoSmithKline, AstraZeneca, Novartis, Lapharcon and EURECA VZW, travel support from GlaxoSmithKline, and acts as chair of the operational Committee IRC (International Respiratory Coalition) for the European Respiratory Society, outside the submitted work. G.G. Brusselle reports advisory board participation and lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merch Sharp & Dohme, Novartis and Sanofi, outside the submitted work. P.M. Hansbro reports grants from the National Health and Medical Research Council (APP1138004, Defining the roles and targeting interferon-epsilon as a new therapy for influenza in asthma and COPD; and APP1179092, Development of a novel effective therapy for asthma and COPD), outside the submitted work.

Comment in

COPD pathophysiology: climbing the waterfall of cell death to find a target.
Cataldo D. Cataldo D. Eur Respir J. 2023 Apr 1;61(4):2300093. doi: 10.1183/13993003.00093-2023. Print 2023 Apr. Eur Respir J. 2023. PMID: 37003614 No abstract available.

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RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD

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RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD

Authors

Affiliations

Abstract

Conflict of interest statement

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