Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages. - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue Journal of Clinical Investigation Année : 2015

Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.

Résumé

Cherubism is a rare autoinflammatory bone disorder that is associated with point mutations in the SH3-domain binding protein 2 (SH3BP2) gene, which encodes the adapter protein 3BP2. Individuals with cherubism present with symmetrical fibro-osseous lesions of the jaw, which are attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although it is a dominant trait in humans, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that macrophages from 3BP2-deficient mice exhibited dramatically reduced in ammatory responses to microbial challenge and reduced phagocytosis. 3BP2 was necessary for LPS-induced activation of signaling pathways involved in macrophage function, including SRC, VAV1, p38MAPK, IKKα/β, RAC, and actin polymerization pathways. Conversely, we demonstrated that the presence of a single Sh3bp2 cherubic allele and pathogen-associated molecular pattern (PAMP) stimulation had a strong cooperative effect on macrophage activation and inflammatory responses in mice. Together, the results from our study in murine genetic models support the notion that infection may represent a driver event in the etiology of cherubism in humans and suggest limiting inflammation in affected individuals may reduce manifestation of cherubic lesions.
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Dates et versions

hal-01295441 , version 1 (31-03-2016)

Identifiants

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Virginie Prod'Homme, Laurent Boyer, Nicholas Dubois, Aude Mallavialle, Patrick Munro, et al.. Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.. Journal of Clinical Investigation, 2015, 125 (4), pp.1396-1400. ⟨10.1172/JCI71081⟩. ⟨hal-01295441⟩
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