Opposing roles of LTB4 and PGE2 in regulating the inflammasome dependent scorpion venom induced mortality
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K+ efflux. Mechanistically, TsV triggers lung resident cells to release PGE2, which induces IL 1b production via E prostanoid receptor 2/4 cAMP PKA NFkB dependent mechanisms. IL 1b/IL 1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL 1b/IL 1R signalling. Activation of LTB4 BLT1/2 pathway decreases cAMP generation, controlling TsV induced inflammation. Exogenous administration confirms LTB4 anti inflammatory activity and abrogates TsV induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL 1b inflammasome dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
Nature communications