Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease.

Lu, Z; Van Eeckhoutte, HP; Liu, G; Nair, PM; Jones, B; Gillis, CM; Nalkurthi, BC; Verhamme, F; Buyle-Huybrecht, T; Vandenabeele, P; Vanden Berghe, T; Brusselle, GG; Horvat, JC; Murphy, JM; Wark, PA; Bracke, KR; Fricker, M; Hansbro, PM

Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease.

Lu, Z Van Eeckhoutte, HP Liu, G

Nair, PM Jones, B Gillis, CM Nalkurthi, BC Verhamme, F Buyle-Huybrecht, T Vandenabeele, P Vanden Berghe, T Brusselle, GG Horvat, JC Murphy, JM Wark, PA Bracke, KR Fricker, M Hansbro, PM

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Publisher:: AMER THORACIC SOC
Publication Type:: Journal Article
Citation:: Am J Respir Crit Care Med, 2021, 204, (6), pp. 667-681
Issue Date:: 2021-09-15

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Field	Value	Language
dc.contributor.author	Lu, Z
dc.contributor.author	Van Eeckhoutte, HP
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Nair, PM
dc.contributor.author	Jones, B
dc.contributor.author	Gillis, CM
dc.contributor.author	Nalkurthi, BC
dc.contributor.author	Verhamme, F
dc.contributor.author	Buyle-Huybrecht, T
dc.contributor.author	Vandenabeele, P
dc.contributor.author	Vanden Berghe, T
dc.contributor.author	Brusselle, GG
dc.contributor.author	Horvat, JC
dc.contributor.author	Murphy, JM
dc.contributor.author	Wark, PA
dc.contributor.author	Bracke, KR
dc.contributor.author	Fricker, M
dc.contributor.author	Hansbro, PM
dc.date.accessioned	2022-03-29T03:11:35Z
dc.date.available	2022-03-29T03:11:35Z
dc.date.issued	2021-09-15
dc.identifier.citation	Am J Respir Crit Care Med, 2021, 204, (6), pp. 667-681
dc.identifier.issn	1073-449X
dc.identifier.issn	1535-4970
dc.identifier.uri	http://hdl.handle.net/10453/155657
dc.description.abstract	Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3-/- and Mlkl-/- mice to acute and chronic CS exposure were compared with those of wild-type mice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.
dc.format	Print
dc.language	eng
dc.publisher	AMER THORACIC SOC
dc.relation.ispartof	Am J Respir Crit Care Med
dc.relation.isbasedon	10.1164/rccm.202009-3442OC
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	11 Medical and Health Sciences
dc.subject.classification	Respiratory System
dc.subject.mesh	Airway Remodeling
dc.subject.mesh	Animals
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Disease Progression
dc.subject.mesh	Humans
dc.subject.mesh	Inflammation
dc.subject.mesh	Linear Models
dc.subject.mesh	Mice
dc.subject.mesh	Necroptosis
dc.subject.mesh	Protein Kinases
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Pulmonary Emphysema
dc.subject.mesh	Receptor-Interacting Protein Serine-Threonine Kinases
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Pulmonary Emphysema
dc.subject.mesh	Disease Progression
dc.subject.mesh	Inflammation
dc.subject.mesh	Protein Kinases
dc.subject.mesh	Linear Models
dc.subject.mesh	Case-Control Studies
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Receptor-Interacting Protein Serine-Threonine Kinases
dc.subject.mesh	Airway Remodeling
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Necroptosis
dc.title	Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease.
dc.type	Journal Article
utslib.citation.volume	204
utslib.location.activity	United States
utslib.for	11 Medical and Health Sciences
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
utslib.copyright.status	closed_access	*
dc.date.updated	2022-03-29T03:11:33Z
pubs.issue	6
pubs.publication-status	Published
pubs.volume	204
utslib.citation.issue	6

Abstract:

Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3-/- and Mlkl-/- mice to acute and chronic CS exposure were compared with those of wild-type mice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.

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