RESUMO
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-1ß 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.
Assuntos
Caspase 1/metabolismo , Caspases Iniciadoras/metabolismo , Venenos de Peixe/farmacologia , Inflamassomos/metabolismo , Inflamação/imunologia , Interleucina-1beta/metabolismo , Pulmão/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Peritonite/induzido quimicamente , Receptores de Superfície Celular/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 1/genética , Caspases Iniciadoras/genética , Feminino , Inflamassomos/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Pulmão/enzimologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/enzimologia , Neutrófilos/imunologia , Peritonite/enzimologia , Peritonite/genética , Peritonite/imunologia , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Transdução de SinaisRESUMO
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.
