Dimethyl fumarate ameliorates lipopolysaccharide-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis through enhancing Nrf2 signaling

Abstract

Background: 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 of great interest to us that dimethyl fumarate (DMF) has been shown to have anti-inflammatory effects. The aim of this study was to investigate whether DMF could alleviate lipopolysaccharide(LPS)-induced ALI, and to explore its mechanism of action.

Materials and methods: We established a mice model of ALI with intratracheal instillation of LPS and intraperitoneal injection of DMF to treat ALI. The pathological damage and inflammatory response of lung tissues were observed by hematoxylin and eosin (H&E) staining, ELISA assay and western blot. ATP plus LPS was used for the establishment of ALI in vitro model, the therapeutic effects of DMF was explored by ELISA assay, RT-qPCR, western blot, and flow cytometry, and the therapeutic mechanisms of DMF was explored by administration of Brusatol (BT), a nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor.

Results: We found that intraperitoneal injection of DMF significantly reduced LPS-induced the pulmonary injury, pulmonary edema, and infiltration of inflammatory mediators. In LPS-induced ALI, NLRP3 inflammasome-mediated pyroptosis was markedly activated, followed by cleavage of caspase-1 and GSDMD. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and ATP plus LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nrf2, leading to inactivation of NLRP3 inflammasome and reduced pyroptosis in vivo and in vitro. Conversely, BT reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI.

Conclusions: 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.

Keywords: NLRP3 inflammasome; Nrf2; acute lung injury; dimethyl fumarate; pyroptosis.