Opposing roles of LTB4 and PGE(2) in regulating the inflammasome-dependent scorpion venom-induced mortality

Author(s)

Zoccal, Karina F. ^[1] ; Sorgi, Carlos A. ^[1] ; Hori, Juliana I. ^[2] ; Paula-Silva, Francisco W. G. ^[1] ; Arantes, Eliane C. ^[3] ; Serezani, Carlos H. ^[4] ; Zamboni, Dario S. ^[2] ; Faccioli, Lucia H. ^[1]

Affiliation

^[1] Univ Sao Paulo FCFRP USP, Dept Anal Clin Toxicol & Bromatol, BR-14040903 Sao Paulo - Brazil

^[2] Univ Sao Paulo FMRP USP, Dept Biol Celular Mol & Bioagentes Patogen, BR-14040903 Sao Paulo - Brazil

^[3] Univ Sao Paulo FCFRP USP, Dept Fis & Quim, BR-14040903 Sao Paulo - Brazil

^[4] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 - USA

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 7, FEB 2016.
• Web of Science Citations: 30

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 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. (AU)

• FAPESP's process: 14/07125-6 - New functional aspects of eicosanoids
• Grantee: Lúcia Helena Faccioli
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/51023-5 - Role of bacterial potassium transporters in inflammatory activation process and in macrophages response to infection by Legionella pneumophila
• Grantee: Juliana Issa Hori
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/03332-7 - Study of the relationship between inflammasome activation and lipid mediators production with pulmonary inflammation induced by scorpion venom with and without hyaluronidase
• Grantee: Karina Furlani Zoccal
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion
• Grantee: Dario Simões Zamboni
• Support Opportunities: Research Projects - Thematic Grants