Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages
| Autor: | Prod'homme, Virginie, Boyer, Laurent, Dubois, Nicholas, Mallavialle, Aude, Munro, Patrick, Mouska, Xavier, Coste, Isabelle, Rottapel, Robert, Tartare-Deckert, Sophie, Deckert, M. |
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| Přispěvatelé: | Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Fondation pour la Recherche MédicaleFondation de France, ANR-06-MRAR-0013,Chérubisme 3BP2,Physio-pathologie du Chérubisme : Analyse moléculaire et fonctionnelle de la protéine adaptatrice 3BP2/SH3BP2 dans le contrôle de l'homéostasie lymphoïde et osseuse(2006), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Prod'homme, Virginie, Programme Pluriannuel de Recherche sur les Maladies Rares (MRAR) - Physio-pathologie du Chérubisme : Analyse moléculaire et fonctionnelle de la protéine adaptatrice 3BP2/SH3BP2 dans le contrôle de l'homéostasie lymphoïde et osseuse - - Chérubisme 3BP22006 - ANR-06-MRAR-0013 - MRAR - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2015, 125 (4), pp.1396-1400. ⟨10.1172/JCI71081⟩ Journal of Clinical Investigation, 2015, 125 (4), pp.1396-1400. ⟨10.1172/JCI71081⟩ |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/JCI71081⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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