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Interleukin-1β (IL-1β) is important for the pathological process of heatstroke (HS), although little is known regarding the main source of the IL-1β produced during the early stage of HS. In this study, heat stress led splenic lymphocytes to death with generation of inflammatory cytokines. The same phenomenon also occurs in animal models of heatshock. We observed that the death of splenic lymphocytes was identified to be pyroptosis. In addition, splenic lymphocyte pyroptosis can be induced by hyperpyrexia in a time- and temperature-dependent manner with NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An NLRP3 inhibitor (MCC950) and a caspase-1 inhibitor (ac-YVAD-cmk) were used to confirm the role of the NLRP3/caspase-1 pathway in pyroptosis. With heat stress, levels of mitochondrial reactive oxygen species (mtROS) in splenic lymphocytes would significantly increase. Accordingly, the use of mtROS scavenger (Mito-TEMPO) could reduce the occurrence of pyroptosis and the activation of the NLRP3 inflammasome  in vitro . In animal models of heatshock, Mito-TEMPO can inhibit activation of the NLRP3/caspase-1 pathway. Taken together, our data suggest that activation of the NLRP3 inflammasome mediates hyperpyrexia-induced pyroptosis in splenic lymphocytes. Perhaps one of the important initiators of pyroptosis is mtROS. Our data have elucidated a new molecular mechanism of IL-1β overexpression in the early stage of HS, providing a new strategy for IL-1β-targeted therapy in future clinical treatments for HS.

frontiers in immunology

The Increase in IL-1β in the Early Stage of Heatstroke Might Be Caused by Splenic Lymphocyte Pyroptosis Induced by mtROS-Mediated Activation of the NLRP3 Inflammasome