Necroptosis signalling promotes inflammation, airway remodelling and emphysema in COPD
- Author(s)
- Lu, Z; Van Eeckhoutte, HP; Liu, G; Nair, PM; JONES, B; Gillis, CM; Nalkurthi, BC; Verhamme, F; Buyle-Huybrecht, T; Vandenabeele, P; Berghe, TV; Brusselle, GG; Murphy, JM; Wark, PA; Bracke, KR; Fricker, M; Hansbro, PM;
- Details
- Publication Year 2021-06-16,Volume 204,Issue #6,Page 667-681
- Journal Title
- American Journal of Respiratory and Critical Care Medicine
- Abstract
- RATIONALE: 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. OBJECTIVES: To determine the role of necroptosis in COPD. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.
- Publisher
- ATS
- Keywords
- COPD; Necroptosis; Apoptosis; remodelling; emphysema
- Research Division(s)
- Inflammation
- PubMed ID
- 34133911
- Publisher's Version
- https://doi.org/10.1164/rccm.202009-3442OC
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2021-06-21 10:26:01
Last Modified: 2022-06-21 11:37:11