LSC - 2019 - Role of necroptosis in the pathogenesis of COPD

Background: Necroptosis is an inflammatory type of regulated cell death, mediated by receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). COPD involves airway inflammation and loss of alveolar tissue (emphysema), as a consequence of cigarette smoke (CS) inhalation. There is evidence that CS-induced necroptosis contributes to the pathogenesis of COPD. Objectives: We investigated the presence of necroptotic markers in human COPD. To assess the contribution of necroptosis to pulmonary inflammation, airway remodelling and emphysema, we chronically exposed RIPK3- and MLKL-deficient mice to CS. Methods: Protein expression levels of RIPK3 and (phosphorylated) MLKL in lungs of never smokers, smokers without airflow obstruction and COPD patients (GOLD II to IV) were evaluated by immunohistochemistry (IHC) and immunoblotting. Wild-type, RIPK3- and MLKL-deficient mice were exposed to CS for 8 weeks. BALF was collected and total and differential leukocytes were enumerated, and histology of lung tissue was assessed. Results: IHC of human lungs revealed positive staining for RIPK3 and MLKL, primarily in airway epithelial cells. Quantification demonstrated increased expression of MLKL but not RIPK3 in airway epithelium of COPD patients, compared to smokers and never smokers. In addition, phosphorylation of MLKL was increased in lung tissue of patients with severe COPD. RIPK3- and MLKL-deficient mice were protected against inflammation in experimental COPD, and both strains showed protection against CS-induced airway remodelling and emphysema, compared to wild-type controls. Conclusions: We provide evidence that necroptosis contributes to the pathogenesis of chronic disease features of COPD.