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 IL-1β 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-1α, 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.
Keywords:
Aerolysin; Caspase-11/caspase-1; IL-1α/β; NLPR6/NLRC4; Natterin; Neutrophilia.
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Caspase 1 / genetics
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Caspase 1 / metabolism*
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Caspases, Initiator / genetics
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Caspases, Initiator / metabolism*
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Female
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Fish Venoms / pharmacology*
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Inflammasomes / immunology
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Inflammasomes / metabolism*
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Inflammation / immunology*
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Inflammation Mediators / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lung / drug effects*
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Lung / enzymology
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Lung / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophil Infiltration / drug effects*
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Neutrophils / drug effects*
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Neutrophils / enzymology
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Neutrophils / immunology
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Peritonitis / chemically induced*
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Peritonitis / enzymology
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Peritonitis / genetics
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Peritonitis / immunology
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Phosphate-Binding Proteins / genetics
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Phosphate-Binding Proteins / metabolism
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Pore Forming Cytotoxic Proteins
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism*
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Signal Transduction
Substances
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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Fish Venoms
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Gsdmd protein, mouse
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IL1B protein, mouse
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Inflammasomes
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Inflammation Mediators
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Ipaf protein, mouse
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Nod-like receptor pyrin domain-containing protein 6, mouse
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Phosphate-Binding Proteins
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Pore Forming Cytotoxic Proteins
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Pycard protein, mouse
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Receptors, Cell Surface
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natterin
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Casp4 protein, mouse
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Caspases, Initiator
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Casp1 protein, mouse
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Caspase 1