Melatonin attenuates chronic obstructive pulmonary disease by suppressing NLRP3-mediated pyroptosis in alveolar macrophages

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and emphysema and is induced primarily by cigarette smoke (CS) exposure. Emerging evidence suggests that alveolar macrophage (AM) Pyroptosis contributes to COPD pathogenesis; however, the underlying mechanisms are incompletely understood. Moreover, although melatonin is known to have therapeutic potential for COPD, whether the regulation of AM Pyroptosis contributes to its therapeutic effects remains unclear. Here, we investigated the mechanism by which AM Pyroptosis participates in COPD airway inflammation and the effect of melatonin in CS-induced COPD model mice and cigarette smoke extract (CSE)-stimulated MH-S cells. Our in vivo experiments revealed that melatonin treatment improved lung function and alleviated emphysema and airway inflammation in COPD mice. Additionally, elevated AM Pyroptosis and increased NLRP3 inflammasome activation were observed in COPD mice, and both of these changes were mitigated by melatonin treatment. Further in vitro experiments demonstrated that melatonin inhibited NLRP3 inflammasome activation in MH-S cells. Importantly, melatonin also suppressed CSE-induced Pyroptosis, as evidenced by improved membrane integrity (lower proportion of PI-positive cells and reduced LDH release), decreased levels of IL-1β and IL-18, and downregulated GSDMD-N expression. Notably, the NLRP3 Inhibitor MCC950 reversed CSE-induced inflammation and Pyroptosis, and the protective effect of melatonin was offset by treatment with the NLRP3 Antagonist nigericin. Taken together, our results suggest that melatonin alleviates airway inflammation in COPD possibly by inhibiting NLRP3-mediated Pyroptosis in AMs, thereby implicating AM Pyroptosis in the pathogenesis of COPD and highlighting melatonin's potential as a therapeutic candidate.

Alveolar macrophages; Chronic obstructive pulmonary disease; Inflammation; Melatonin; NLRP3 inflammasome; Pyroptosis.