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

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

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 13, p. 16-pg., 2022-06-21.

Abstract

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-1 beta, 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-1 beta 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-beta production by stimulated macrophages and the E19K ASC mutation carried by AIRmin mice impaired the ex vivo IL-1 beta response and the formation of ASC specks in stimulated cells. IL-1 beta 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. (AU)

• FAPESP's process: 17/06736-0 - Identification/elucidation and validation of new targets/pathways involved in osteoarthritis
• Grantee: Jean Gabriel de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/13139-0 - Centre of Excellence in New Target Discovery
• Grantee: Ana Marisa Chudzinski-Tavassi
• Support Opportunities: Research Grants - Research Centers in Engineering Program