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

Autor(es)

Lima, Carla ; Andrade-Barros, Aline Ingrid ; Goncalves Bernardo, Jefferson Thiago ; Balogh, Eniko ; Quesniaux, Valerie F. ; Ryffel, Bernhard ; Lopes-Ferreira, Monica

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 7, p. 15-pg., 2022-04-01.

Resumo

Natterin is a potent pro-inflammatory fish molecule, inducing local and systemic IL-1 beta/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 ifn gamma r 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. (AU)

• Processo FAPESP: 18/17413-0 - Avaliação do papel do inflamassome na inflamação neutrofílica induzida por toxinas formadoras de poros, Natterins
• Beneficiário: Carla Lima da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/10500-7 - Avaliação da necessidade da ativação do complexo inflamassoma na inflamação neutrofilica induzida pelas natterinas, toxinas formadoras de poros
• Beneficiário: Carla Lima da Silva
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 21/06084-8 - Avaliação da importância funcional de proteínas da família Natterin na ativação do inflamassoma em zebrafish
• Beneficiário: Carla Lima da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
• Beneficiário: Hugo Aguirre Armelin
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs