Pycard and BC017158 candidate genes of irm1 locus modulate inflammasome activation for IL-1β production

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dc.contributorLab. Imunogenéticapt_BR
dc.contributor(CENTD) Centro de Excelência para Descoberta de Alvos Molecularespt_BR
dc.contributorLab. Imunopatologiapt_BR
dc.contributor(LDI) Lab. Desenvolvimento e Inovação Industrialpt_BR
dc.contributorPrograma de Pós-Graduação em Ciências – Toxinologia (PPGTox)pt_BR
dc.contributorPrograma de Pós-Doutoradopt_BR
dc.contributor.authorBorrego, Andreapt_BR
dc.contributor.authorColombo, Francescapt_BR
dc.contributor.authorSouza, Jean Gabriel dept_BR
dc.contributor.authorJensen, José Ricardopt_BR
dc.contributor.authorRibeiro, Orlando Garciapt_BR
dc.contributor.authorCabrera, Wafa Hanna Kourypt_BR
dc.contributor.authorStarobinas, Nancypt_BR
dc.contributor.authorMagalhães, Geraldo Santanapt_BR
dc.contributor.authorEto, Silas Fernandespt_BR
dc.contributor.authorDe Ocesano-Pereira, Carlospt_BR
dc.contributor.authorGoldfeder, Mauricio Barbugianipt_BR
dc.contributor.authorPasqualoto, Kerly Fernanda Mesquitapt_BR
dc.contributor.authorIbañez, Olga Célia Martinezpt_BR
dc.identifier.citationBorrego A, Colombo F, Souza JG, Jensen JR, Dassano A, Piazza R, et al. Pycard and BC017158 candidate genes of irm1 locus modulate inflammasome activation for IL-1β production. Front. Immunol. 2022 June;13:899569. doi:10.3389/fimmu.2022.899569.pt_BR
dc.description.abstractWe identified Pycard and BC017158 genes as putative effectors of the Quantitative Trait locus (QTL) that we mapped at distal chromosome 7 named Irm1 for Inflammatory response modulator 1, controlling acute inflammatory response (AIR) and the production of IL-1β, dependent on the activation of the NLRP3 inflammasome. We obtained the mapping through genome-wide linkage analysis of Single Nucleotide Polymorphisms (SNPs) in a cross between High (AIRmax) and Low (AIRmin) responder mouse lines that we produced by several generations of bidirectional selection for Acute Inflammatory Response. A highly significant linkage signal (LOD score peak of 72) for ex vivo IL-1β production limited a 4 Mbp interval to chromosome 7. Sequencing of the locus region revealed 14 SNPs between “High” and “Low” responders that narrowed the locus to a 420 Kb interval. Variants were detected in non-coding regions of Itgam, Rgs10 and BC017158 genes and at the first exon of Pycard gene, resulting in an E19K substitution in the protein ASC (apoptosis associated speck-like protein containing a CARD) an adaptor molecule in the inflammasome complex. Silencing of BC017158 inhibited IL1-β production by stimulated macrophages and the E19K ASC mutation carried by AIRmin mice impaired the ex vivo IL-1β response and the formation of ASC specks in stimulated cells. IL-1β and ASC specks play major roles in inflammatory reactions and in inflammation-related diseases. Our results delineate a novel genetic factor and a molecular mechanism affecting the acute inflammatory response.pt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.description.sponsorship(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.relation.ispartofFrontiers in Immunologypt_BR
dc.rightsOpen accesspt_BR
dc.titlePycard and BC017158 candidate genes of irm1 locus modulate inflammasome activation for IL-1β productionpt_BR
dc.rights.licenseCC BYpt_BR
dc.contributor.external(INT/Fondazione IRCCS) Istituto Nazionale dei Tumoript_BR
dc.contributor.externalUniversity of Milano-Bicoccapt_BR
dc.contributor.externalInstituto Pasteurpt_BR
dc.contributor.external(UNIFESP) Universidade Federal de São Paulopt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.subject.keywordgenome screeningpt_BR
dc.subject.keywordASC speckspt_BR
dc.relation.ispartofabbreviatedFront Immunolpt_BR
dc.identifier.citationabntv. 13, 899569, jun. 2022pt_BR
dc.identifier.citationvancouver2022 June;13:899569pt_BR
dc.contributor.butantanBorrego, Andrea|:Pesquisador|:Lab. Imunogenética|:PrimeiroAutorpt_BR
dc.contributor.butantanJensen, José Ricardo|:Pesquisador|:Lab. Imunogenéticapt_BR
dc.contributor.butantanRibeiro, Orlando Garcia|:Pesquisador|:Lab. Imunogenéticapt_BR
dc.contributor.butantanCabrera, Wafa Hanna Koury|:Pesquisador|:Lab. Imunogenéticapt_BR
dc.contributor.butantanStarobinas, Nancy|:Pesquisador|:Lab. Imunogenéticapt_BR
dc.contributor.butantanMagalhães, Geraldo Santana|:Pesquisador:Docente Permanente PPGTox|:Lab. Imunopatologiapt_BR
dc.contributor.butantanEto, Silas Fernandes|:Outros|:Lab. Desenvolvimento e Inovação Industrialpt_BR
dc.contributor.butantanDe Ocesano-Pereira, Carlos|:Pesquisador|:(CENTD) Centro de Excelência para Descoberta de Alvos Molecularespt_BR
dc.contributor.butantanGoldfeder, Mauricio Barbugiani|:Técnico|:(LDI) (LDI) Lab. Desenvolvimento e Inovação Industrialpt_BR
dc.contributor.butantanIbañez, Olga Célia Martinez|:Pesquisador|:Lab. Imunogenética|:Autor de correspondênciapt_BR
dc.contributor.butantanPasqualoto, Kerly Fernanda Mesquita|:Egresso Pós-Doc|:Programa de Pós-Doutoradopt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2016/07007- 9pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2020/13139-0pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2017/06736-0pt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico¦¦pt_BR
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