AUTHOR=Borrego Andrea , Colombo Francesca , de Souza Jean Gabriel , Jensen José Ricardo , Dassano Alice , Piazza Rocco , Rodrigues dos Santos Barbara Anaís , Ribeiro Orlando Garcia , De Franco Marcelo , Cabrera Wafa Hanna Koury , Icimoto Marcelo Yudi , Starobinas Nancy , Magalhães Geraldo , Monteleone Leticia Figueiredo , Eto Silas Fernandes , DeOcesano-Pereira Carlos , Goldfeder Mauricio Barbugiani , Pasqualoto Kerly Fernanda Mesquita , Dragani Tommaso A. , Ibañez Olga Célia Martinez 

TITLE=Pycard and BC017158 Candidate Genes of Irm1 Locus Modulate Inflammasome Activation for IL-1β Production

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.899569

DOI=10.3389/fimmu.2022.899569

ISSN=1664-3224

ABSTRACT=<p>We identified <italic>Pycard</italic> and <italic>BC017158</italic> genes as putative effectors of the Quantitative Trait locus (QTL) that we mapped at distal chromosome 7 named <italic>Irm1</italic> 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 <italic>ex vivo</italic> 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 <italic>Itgam</italic>, <italic>Rgs10</italic> and <italic>BC017158</italic> genes and at the first exon of <italic>Pycard</italic> 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 <italic>BC017158</italic> inhibited IL1-β production by stimulated macrophages and the E19K ASC mutation carried by AIRmin mice impaired the <italic>ex vivo</italic> 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.</p>