Natterin an aerolysin-like fish toxin drives IL-1 beta-dependent neutrophilic inflammation mediated by caspase-1 and caspase-11 activated by the inflammasome sensor NLRP6

Author(s)

Lima, Carla ^[1] ; Falcao, Maria Alice Pimentel ^[1] ; Andrade-Barros, Aline Ingrid ^[1] ; Seni-Silva, Ana Carolina ^[1] ; Grund, Lidiane Zito ^[1] ; Balogh, Eniko ^[2] ; Conceicao, Katia ^[3] ; Queniaux, Valerie F. ^{[4, 5]} ; Ryffel, Bernhard ^{[4, 5]} ; Lopes-Ferreira, Monica ^[1]

Affiliation

^[1] Butantan Inst, Immunoregulat Unit Lab Appl Toxinol CETICs FAPESP, Vital Brazil Ave 1500, BR-05503009 Sao Paulo, SP - Brazil

^[2] Univ Debrecen, Res Ctr Mol Med, Fac Med, Nagyerdei Krt 98, H-4012 Debrecen - Hungary

^[3] UNIFESP, Peptide Biochem Lab, Sao Jose Dos Campos - Brazil

^[4] Univ Orleans, F-45071 Orleans 2 - France

^[5] CNRS, UMR7355, Allergy & Lung Inflammat Unit Mol & Expt Immunol, F-45071 Orleans 2 - France

• Document type: Journal article
• Source: International Immunopharmacology; v. 91, FEB 2021.
• Web of Science Citations: 0

Abstract

Natterin is an aerolysin-like pore-forming toxin responsible for the toxic effects of the venom of the medically significant fish Thalassophryne nattereri. Using a combination of pharmacologic and genetic loss-of-function approaches we conduct a systematic investigation of the regulatory mechanisms that control Natterin-induced neutrophilic inflammation in the peritonitis model. Our data confirmed the capacity of Natterin to induce a strong and sustained neutrophilic inflammation leading to systemic inflammatory lung infiltration and revealed overlapping regulatory paths in its control. We found that Natterin induced the extracellular release of mature IL1 beta and the sustained production of IL-33 by bronchial epithelial cells. We confirmed the dependence of both ST2/IL-33 and IL-17A/IL-17RA signaling on the local and systemic neutrophils migration, as well as the crucial role of IL-1 alpha, caspase-1 and caspase-11 for neutrophilic inflammation. The inflammation triggered by Natterin was a gasdermin-D-dependent inflammasome process, despite the cells did not die by pyroptosis. Finally, neutrophilic inflammation was mediated by non-canonical NLRP6 and NLRC4 adaptors through ASC interaction, independent of NLRP3. Our data highlight that the inflammatory process dependent on non-canonical inflammasome activation can be a target for pharmacological intervention in accidents by T. nattereri, which does not have adequate specific therapy. (AU)

• FAPESP's process: 18/17413-0 - Evaluation of inflammasome requirement in neutrophilic inflammation induced by pore-forming toxins, Natterins
• Grantee: Carla Lima da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/10500-7 - EVALUATION OF INFLAMMASOME REQUIREMENT IN NEUTROPHILIC INFLAMMATION INDUCED BY PORE-FORMING TOXINS, NATTERINS
• Grantee: Carla Lima da Silva
• Support Opportunities: Scholarships abroad - Research
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC