Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10760
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Funding
- Sao Paulo Research Foundation (FAPESP) [2014/07125-6, 2014/04684-4, 2014/03332-7, 2011/51023-5]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- NIH [HL-103777, R01HL124159-01]
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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 PGE(2), which induces IL-1 beta production via E prostanoid receptor 2/4-cAMP-PKA-NF kappa B-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 PGE(2) via IL-1 beta/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-1 beta inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation.
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