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- Title
Necroptosis Signalling Promotes Inflammation, Airway Remodelling and Emphysema in COPD.
- Authors
Zhe Lu; Van Eeckhoutte, Hannelore P.; Gang Liu; Nair, Prema M.; Jones, Bernadette; Gillis, Caitlin M.; Nalkurthi, B. Christina; Verhamme, Fien; Buyle-Huybrecht, Tamariche; Vandenabeele, Peter; Berghe, Tom Vanden; Brusselle, Guy G.; Horvat, Jay C.; Murphy, James M.; Wark, Peter A.; Bracke, Ken R.; Fricker, Michael; Hansbro, Philip M.; Lu, Zhe; Liu, Gang
- Abstract
<bold>Rationale: </bold>Necroptosis, mediated by RIPK3 and MLKL, is a form of regulated necrosis that can drive tissue inflammation and destruction, however its contribution to COPD pathogenesis is poorly understood.<bold>Objectives: </bold>To determine the role of necroptosis in COPD.<bold>Methods: </bold>Levels of RIPK3, MLKL and activated phospho-MLKL were measured in lung tissues of COPD patients and non-COPD controls. Necroptosis-related mRNA and proteins and cell death were examined in the lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3- and Mlkl-deficient (-/-) mice to CS exposure were compared to wild-type mice. Combined inhibition of apoptosis (pan-caspase inhibitor qVD-OPh) and necroptosis (Mlkl-/- mice) was assessed.<bold>Measurements and Main Results: </bold>Protein levels of MLKL and pMLKL but not RIPK3 were increased in lung tissues of COPD patients compared to never smokers or smoker non-COPD controls. Necroptosis-related mRNA and protein levels were increased in lung tissue and macrophages in CS-exposed mice/experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation in response to acute CS-exposure. Ripk3 deficiency reduced airway inflammation and remodelling and development of emphysematous pathology following chronic CS-exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodelling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung cell death.<bold>Conclusions: </bold>Necroptosis is induced by CS exposure and increased in COPD patient lungs and experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodelling and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.
- Subjects
CHRONIC obstructive pulmonary disease; APOPTOSIS; INFLAMMATION; MESSENGER RNA; TISSUES
- Publication
American Journal of Respiratory & Critical Care Medicine, 2021, Vol 204, Issue 6, p667
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.202009-3442OC