| Autor: |
Andrea Borrego, Francesca Colombo, Jean Gabriel de Souza, José Ricardo Jensen, Alice Dassano, Rocco Piazza, Barbara Anaís Rodrigues dos Santos, Orlando Garcia Ribeiro, Marcelo De Franco, Wafa Hanna Koury Cabrera, Marcelo Yudi Icimoto, Nancy Starobinas, Geraldo Magalhães, Leticia Figueiredo Monteleone, Silas Fernandes Eto, Carlos DeOcesano-Pereira, Mauricio Barbugiani Goldfeder, Kerly Fernanda Mesquita Pasqualoto, Tommaso A. Dragani, Olga Célia Martinez Ibañez |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Frontiers in Immunology, Vol 13 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1664-3224 |
| DOI: |
10.3389/fimmu.2022.899569 |
| Popis: |
We 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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