Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is established that Dimethyl fumarate (DMF) exhibits anti inflammatory effects, however, the specific effect of DMF on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, DMF alleviated lipopolysaccharide (LPS)-induced ALI. We found that intraperitoneal injection of DMF markedly reduced the pulmonary injury, decreased pulmonary edema and pulmonary permeability. Emerging studies suggested that the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis played a critical role during ALI. NLRP3 inflammasome-mediated pyroptosis is significantly activated with the cleavage of caspase-1 and GSDMD occurring in the lung of LPS-induced ALI. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nuclear factor erythroid-2-related factor 2 (Nrf2), leading to inactivation of NLRP3 inflammasome and reduction of pyroptosis in both ALI mice and LPS-induced BEAS-2B cells. Conversely, Nrf2 inhibitor reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI in mice. This study for the first time demonstrated that DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.