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Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway

Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1β/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulti...

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Autores principales: Lima, Carla, Andrade-Barros, Aline Ingrid, Bernardo, Jefferson Thiago Gonçalves, Balogh, Eniko, Quesniaux, Valerie F., Ryffel, Bernhard, Lopes-Ferreira, Monica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998820/
https://www.ncbi.nlm.nih.gov/pubmed/35408954
http://dx.doi.org/10.3390/ijms23073600
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author Lima, Carla
Andrade-Barros, Aline Ingrid
Bernardo, Jefferson Thiago Gonçalves
Balogh, Eniko
Quesniaux, Valerie F.
Ryffel, Bernhard
Lopes-Ferreira, Monica
author_facet Lima, Carla
Andrade-Barros, Aline Ingrid
Bernardo, Jefferson Thiago Gonçalves
Balogh, Eniko
Quesniaux, Valerie F.
Ryffel, Bernhard
Lopes-Ferreira, Monica
author_sort Lima, Carla
collection PubMed
description Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1β/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulting in self-DNA leaks into the cytosol, and whether the DNA sensor cGAS and STING pathway participate in triggering the innate immune response. Employing a peritonitis mouse model, we found that the deficiency of the tlr2/tlr4, myd88 and trif results in decreased neutrophil influx to peritoneal cavities of mice, indicative that in addition to MyD88, TRIF contributes to neutrophilia triggered by TLR4 engagement by Natterin. Next, we demonstrated that gpcr91 deficiency in mice abolished the neutrophil recruitment after Natterin injection, but mice pre-treated with 2-deoxy-d-glucose that blocks glycolysis presented similar infiltration than WT Natterin-injected mice. In addition, we observed that, compared with the WT Natterin-injected mice, DPI and cyclosporin A treated mice had a lower number of neutrophils in the peritoneal exudate. The levels of dsDNA in the supernatant of the peritoneal exudate and processed IL-33 in the supernatant of the peritoneal exudate or cytoplasmic supernatant of the peritoneal cell lysate of WT Natterin-injected mice were several folds higher than those of the control mice. The recruitment of neutrophils to peritoneal cavity 2 h post-Natterin injection was intensely impaired in ifnar KO mice and partially in il-28r KO mice, but not in ifnγr KO mice. Finally, using cgas KO, sting KO, or irf3 KO mice we found that recruitment of neutrophils to peritoneal cavities was virtually abolished in response to Natterin. These findings reveal cytosolic DNA sensors as critical regulators for Natterin-induced neutrophilia.
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spelling pubmed-89988202022-04-12 Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway Lima, Carla Andrade-Barros, Aline Ingrid Bernardo, Jefferson Thiago Gonçalves Balogh, Eniko Quesniaux, Valerie F. Ryffel, Bernhard Lopes-Ferreira, Monica Int J Mol Sci Article Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1β/IL-1R1-dependent neutrophilia mediated by non-canonical NLRP6 and NLRC4 inflammasome activation in mice, independent of NLRP3. In this work, we investigated whether Natterin activates mitochondrial damage, resulting in self-DNA leaks into the cytosol, and whether the DNA sensor cGAS and STING pathway participate in triggering the innate immune response. Employing a peritonitis mouse model, we found that the deficiency of the tlr2/tlr4, myd88 and trif results in decreased neutrophil influx to peritoneal cavities of mice, indicative that in addition to MyD88, TRIF contributes to neutrophilia triggered by TLR4 engagement by Natterin. Next, we demonstrated that gpcr91 deficiency in mice abolished the neutrophil recruitment after Natterin injection, but mice pre-treated with 2-deoxy-d-glucose that blocks glycolysis presented similar infiltration than WT Natterin-injected mice. In addition, we observed that, compared with the WT Natterin-injected mice, DPI and cyclosporin A treated mice had a lower number of neutrophils in the peritoneal exudate. The levels of dsDNA in the supernatant of the peritoneal exudate and processed IL-33 in the supernatant of the peritoneal exudate or cytoplasmic supernatant of the peritoneal cell lysate of WT Natterin-injected mice were several folds higher than those of the control mice. The recruitment of neutrophils to peritoneal cavity 2 h post-Natterin injection was intensely impaired in ifnar KO mice and partially in il-28r KO mice, but not in ifnγr KO mice. Finally, using cgas KO, sting KO, or irf3 KO mice we found that recruitment of neutrophils to peritoneal cavities was virtually abolished in response to Natterin. These findings reveal cytosolic DNA sensors as critical regulators for Natterin-induced neutrophilia. MDPI 2022-03-25 /pmc/articles/PMC8998820/ /pubmed/35408954 http://dx.doi.org/10.3390/ijms23073600 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lima, Carla
Andrade-Barros, Aline Ingrid
Bernardo, Jefferson Thiago Gonçalves
Balogh, Eniko
Quesniaux, Valerie F.
Ryffel, Bernhard
Lopes-Ferreira, Monica
Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title_full Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title_fullStr Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title_full_unstemmed Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title_short Natterin-Induced Neutrophilia Is Dependent on cGAS/STING Activation via Type I IFN Signaling Pathway
title_sort natterin-induced neutrophilia is dependent on cgas/sting activation via type i ifn signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998820/
https://www.ncbi.nlm.nih.gov/pubmed/35408954
http://dx.doi.org/10.3390/ijms23073600
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