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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 7, FEB 2016.
• Citações Web of Science: 30

Resumo

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)

• Processo FAPESP: 14/07125-6 - Novos aspectos funcionais dos eicosanóides
• Beneficiário: Lúcia Helena Faccioli
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/51023-5 - O papel de transportadores de potássio bacterianos no processo de ativação do inflamassoma e na resposta de macrófagos a infecção por Legionella pneumophila
• Beneficiário: Juliana Issa Hori
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/03332-7 - Estudo da relação entre ativação do inflamassoma e produção de mediadores lipídicos com a inflamação pulmonar induzida por veneno de escorpião com e sem hialuronidase
• Beneficiário: Karina Furlani Zoccal
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/04684-4 - O inflamassoma na resposta contra patógenos intracelulares e os mecanismos microbianos relacionados à evasão
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Temático