Gasdermin D-dependent macrophage pyroptosis mediates polystyrene microplastics-induced pulmonary fibrosis

Exposure to microplastic (MPs) pollution may induce pulmonary fibrosis (PF). Macrophage pyroptosis has been directly implicated in the pathogenesis of PF. This study focused on the potential driving role of macrophage pyroptosis in polystyrene microplastics (PS-MPs) induced pulmonary fibrosis. Through a 56-day intranasal exposure model in mice, we demonstrate that chronic exposure to 5-μm PS-MPs induces significant pulmonary fibrosis characterized by collagen deposition, extracellular matrix remodeling, and substantial lung function impairment. PS-MPs specifically trigger GSDMD-dependent pyroptosis in alveolar macrophages, as evidenced by enhanced NLRP3 inflammasome assembly, caspase-1 activation, and GSDMD-NT pore formation. Genetic ablation of Gsdmd substantially attenuated fibrotic progression, improved pulmonary functional parameters, and reduced production of pro-fibrotic mediators including IL-1β. Crucially, we established a direct paracrine link between macrophage pyroptosis and fibrogenesis through conditioned medium experiments, demonstrating that GSDMD-dependent release of pyroptotic factors promotes fibroblast activation and extracellular matrix production. Our results delineate a complete pathogenic pathway wherein PS-MPs induce pulmonary fibrosis through macrophage pyroptosis, thereby positioning GSDMD as both a key mediator and promising therapeutic target for combating microplastic-associated lung disease. These findings provide crucial insights into the environmental health risks of microplastics and identify potential intervention strategies for plastic pollution-related respiratory disorders.