title: Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages.
abstract: 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 inflammatory 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.
authors.forename: Virginie
authors.initials: V
authors.lastname: Prod'Homme
authors.forename: Laurent
authors.initials: L
authors.lastname: Boyer
authors.forename: Nicholas
authors.initials: N
authors.lastname: Dubois
authors.forename: Aude
authors.initials: A
authors.lastname: Mallavialle
authors.forename: Patrick
authors.initials: P
authors.lastname: Munro
authors.forename: Xavier
authors.initials: X
authors.lastname: Mouska
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coste
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Sophie
authors.initials: S
authors.lastname: Tartare-Deckert
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
mesh_terms: D000199:Actins / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D019264:Adoptive Transfer; D019943:Amino Acid Substitution; D000818:Animals; D002636:Cherubism / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006579:Heterozygote; D006801:Humans; D007249:Inflammation / Q000382:microbiology / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008262:Macrophage Activation / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology; D017354:Point Mutation; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000502:physiology
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D008070:Lipopolysaccharides; C109073:SH3BP2 protein, human; C484644:Sh3bp2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C482199:lipopolysaccharide, E coli O55-B5