Molecular insights of T-2 toxin exposure-induced neurotoxicity and the neuroprotective effect of dimethyl fumarate

Abstract

T-2 toxin, a potent environmental pollutant, has been proved to stimulate neuroinflammation, while the connection between T-2 toxin and pyroptosis remain elusive. Dimethyl fumarate (DMF), recently identified as a neuroprotectant and pyroptosis inhibitor, has potential therapeutic applications that are underexplored. Based on present study in vitro and vivo, we demonstrated that T-2 toxin induced the activation of NLRP3-Caspase-1 inflammasome in hippocampal neurons. In addition to proinflammatory mediator overexpression, gasdermin D (GSDMD)-dependently pyroptosis in the mouse hippocampal neuron cell line (HT22) treated by T-2 toxin was determined in our study. Moreover, the palliative effect of knockdown sequence of high mobility group B1 protein (HMGB1) provided more details for T-2 toxin-initiated pyroptosis. Importantly, we confirmed that DMF, as a novel inhibitor of GSDMD, could alleviate pyroptosis induced by T-2 toxin in an GSDMD targeting manner. In summary, our studies exposed the evidence that T-2 toxin could induce NLRP3 inflammasome activation and hippocampal neuronal pyroptosis. More notably, DMF was turn out to be a critical executioner for attenuating GSDMD-mediated pyroptosis. Our data found a new function of DMF and suggested a novel therapy strategy against mycotoxin-triggered neuronal inflammation, which leads to varieties of neurological diseases.