Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.

Zoccal KF, Sorgi CA, Hori JI, Paula-Silva FW, Arantes EC, Serezani CH, Zamboni DS, Faccioli LH
Nat Commun. 2016 7: 10760

PMID: 26907476 · PMCID: PMC4766425 · DOI:10.1038/ncomms10760

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-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/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-1β/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-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.

MeSH Terms (31)

Animals Arachidonate 5-Lipoxygenase Blotting, Western Carrier Proteins Celecoxib Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclooxygenase Inhibitors Dinoprostone Indoles Indomethacin Inflammasomes Interleukin-1beta In Vitro Techniques Leukotriene B4 Lipoxygenase Inhibitors Macrophages Macrophages, Peritoneal Mice Mice, Knockout NF-kappa B NLR Family, Pyrin Domain-Containing 3 Protein Phosphoproteins Prostaglandin Antagonists Receptors, Prostaglandin E, EP2 Subtype Receptors, Prostaglandin E, EP4 Subtype Reverse Transcriptase Polymerase Chain Reaction Scorpions Scorpion Stings Scorpion Venoms Xanthones

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