Abstract
Necroptosis has emerged as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we found that markers of necroptosis, including high mobility group box 1 release and phosphorylation of mixed lineage kinase domain-like protein (p-MLKL), were markedly induced in the late stage of cigarette smoking–induced (CS-induced) emphysema in mouse lung tissue as well as in lung epithelial cells and organoids with higher dosage of or more prolonged exposure to cigarette smoking extract (CSE). Apoptotic signals were also detected and maximally induced in the early stage of CS-exposed mice and CSE-treated epithelial cells. Inhibition of apoptosis by Z-VAD, a pan-caspase inhibitor, switched the cellular stress to enhanced necroptosis in lung epithelial cells and organoids treated with CSE. Depletion or inhibition of receptor-interacting protein kinase 3 (RIP3) or MLKL attenuated the CSE-induced cell death, suggesting that necroptosis contributes to CSE-induced cell death. Silencing or inhibition of RIP1 had no protective effect, indicating a RIP1-independent RIP3 activation pathway. CSE-induced necroptosis released more damage-associated molecular patterns and evoked greater engulfment but slower clearance by bone marrow–derived macrophages, leading to enhanced expression of proinflammatory cytokines Tnfα and Il6. Finally, our in vivo data verified that inhibition of necroptosis by RIP3 inhibitor GSK’872 protected mice from CS-induced emphysema and suppressed the lung inflammation. In conclusion, we provide evidence that necroptosis contributes to the pathogenesis of COPD. Targeting RIP3 and its downstream pathway may be an effective therapy for COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) affects more than 10% of the world population over the age of 40 years and ranks as the fourth leading cause of death worldwide [1, 2]
We show that the necroptosis markers phosphorylated mixed lineage kinase domain-like protein (MLKL) (p-MLKL) and high mobility group box 1 (HMGB1) release are markedly elevated in patients with COPD, smoking-exposed mice, and cigarette smoking extract–treated (CSE-treated) lung epithelial cells
To study cell death signals in COPD, we examined the expression of RIP1, receptorinteracting protein kinase 3 (RIP3), MLKL p-MLKL, and cleaved caspase-3 in the lungs of donors and COPD patients (n = 10 for each group)
Summary
Chronic obstructive pulmonary disease (COPD) affects more than 10% of the world population over the age of 40 years and ranks as the fourth leading cause of death worldwide [1, 2]. The identification of molecular mediators that trigger lung responses involving inflammation and alveolar cell death will help develop novel therapies for COPD. Exposure to CS has been reported to induce epithelial cell death by apoptosis and necroptosis, which occur in patients with COPD [7, 8]. Necroptosis is considered a type of programmed cell death involving greater damage-associated molecular pattern (DAMP) release and inflammatory response [9, 10]. The release of inflammatory substances in necroptosis contributes to persistent lung inflammation, which cannot be explained by apoptosis-derived cell death. There is accumulating evidence that necroptosis occurs in patients with COPD [8, 13], but its role in inflammation and disease pathogenesis is unknown
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