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

Van Eeckhoutte, HP; Donovan, C; Kim, RY; Conlon, TM; Ansari, M; Khan, H; Jayaraman, R; Hansbro, NG; Dondelinger, Y; Delanghe, T; Beal, AM; Geddes, B; Bertin, J; Berghe, TV; De Volder, J; Maes, T; Vandenabeele, P; Vanaudenaerde, BM; Deforce, D; Škevin, S; Van Nieuwerburgh, F; Verhamme, FM; Joos, GF; Idrees, S; Schiller, HB; Yildirim, AÖ; Faiz, A; Bertrand, MJM; Brusselle, GG; Hansbro, PM; Bracke, KR

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

Van Eeckhoutte, HP Donovan, C Kim, RY Conlon, TM Ansari, M Khan, H Jayaraman, R Hansbro, NG Dondelinger, Y Delanghe, T Beal, AM Geddes, B Bertin, J Berghe, TV De Volder, J Maes, T Vandenabeele, P Vanaudenaerde, BM Deforce, D Škevin, S Van Nieuwerburgh, F Verhamme, FM Joos, GF Idrees, S Schiller, HB Yildirim, AÖ Faiz, A

Bertrand, MJM Brusselle, GG Hansbro, PM Bracke, KR

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Publisher:: European Respiratory Society (ERS)
Publication Type:: Journal Article
Citation:: Eur Respir J, 2022, pp. 2201506
Issue Date:: 2022-12-22

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Field	Value	Language
dc.contributor.author	Van Eeckhoutte, HP
dc.contributor.author	Donovan, C
dc.contributor.author	Kim, RY
dc.contributor.author	Conlon, TM
dc.contributor.author	Ansari, M
dc.contributor.author	Khan, H
dc.contributor.author	Jayaraman, R
dc.contributor.author	Hansbro, NG
dc.contributor.author	Dondelinger, Y
dc.contributor.author	Delanghe, T
dc.contributor.author	Beal, AM
dc.contributor.author	Geddes, B
dc.contributor.author	Bertin, J
dc.contributor.author	Berghe, TV
dc.contributor.author	De Volder, J
dc.contributor.author	Maes, T
dc.contributor.author	Vandenabeele, P
dc.contributor.author	Vanaudenaerde, BM
dc.contributor.author	Deforce, D
dc.contributor.author	Škevin, S
dc.contributor.author	Van Nieuwerburgh, F
dc.contributor.author	Verhamme, FM
dc.contributor.author	Joos, GF
dc.contributor.author	Idrees, S
dc.contributor.author	Schiller, HB
dc.contributor.author	Yildirim, AÖ
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Bertrand, MJM
dc.contributor.author	Brusselle, GG
dc.contributor.author	Hansbro, PM
dc.contributor.author	Bracke, KR
dc.date.accessioned	2023-02-05T23:55:23Z
dc.date.available	2022-11-28
dc.date.available	2023-02-05T23:55:23Z
dc.date.issued	2022-12-22
dc.identifier.citation	Eur Respir J, 2022, pp. 2201506
dc.identifier.issn	0903-1936
dc.identifier.issn	1399-3003
dc.identifier.uri	http://hdl.handle.net/10453/165910
dc.description.abstract	RATIONALE: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVE: 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 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 Ripk1S25D /S25D kinase deficient mice and the RIPK1 kinase inhibitor GSK'547. MEASUREMENTS AND MAIN RESULTS: RIPK1 expression increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to 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 remodeling, 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-sequencing 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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	European Respiratory Society (ERS)
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation	http://purl.org/au-research/grants/nhmrc/2010287
dc.relation.ispartof	Eur Respir J
dc.relation.isbasedon	10.1183/13993003.01506-2022
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	11 Medical and Health Sciences, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.title	RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD.
dc.type	Journal Article
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	closed_access	*
dc.date.updated	2023-02-05T23:55:17Z
pubs.publication-status	Published online

Abstract:

RATIONALE: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVE: 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 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 Ripk1S25D /S25D kinase deficient mice and the RIPK1 kinase inhibitor GSK'547. MEASUREMENTS AND MAIN RESULTS: RIPK1 expression increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to 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 remodeling, 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-sequencing 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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http://hdl.handle.net/10453/165910