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

Nat Commun. 2016 Feb 23:7:10760. doi: 10.1038/ncomms10760.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Carrier Proteins
  • Cyclooxygenase Inhibitors
  • IL1B protein, mouse
  • Indoles
  • Inflammasomes
  • Interleukin-1beta
  • Lipoxygenase Inhibitors
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Phosphoproteins
  • Prostaglandin Antagonists
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP4 Subtype
  • Scorpion Venoms
  • Xanthones
  • MK-886
  • Leukotriene B4
  • 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
  • Cyclic AMP
  • Arachidonate 5-Lipoxygenase
  • Cyclic AMP-Dependent Protein Kinases
  • Celecoxib
  • Dinoprostone
  • Indomethacin