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

• Published in: The Journal of clinical investigation Vol. 125; no. 4; pp. 1396 - 1400
• Main Authors: Prod'Homme, Virginie, Boyer, Laurent, Dubois, Nicholas, Mallavialle, Aude, Munro, Patrick, Mouska, Xavier, Coste, Isabelle, Rottapel, Robert, Tartare-Deckert, Sophie, Deckert, Marcel
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-04-2015
• Subjects: Actins - chemistry; Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - physiology; Adoptive Transfer; Allelomorphism; Amino Acid Substitution; Animals; Biomedical research; Brief Report; Cherubism - genetics; Cytokines - secretion; Development and progression; Disease; Disease Models, Animal; E coli; Flow cytometry; Gene mutations; Genetic disorders; Genotype & phenotype; Health aspects; Heterozygosis; Heterozygosity; Heterozygote; Humans; Identification and classification; Inflammation - microbiology; Inflammation - physiopathology; Kinases; Life Sciences; Lipopolysaccharides; Macrophage Activation - physiology; Macrophages, Peritoneal - transplantation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis, Site-Directed; Mutation; Mutation, Missense; Osteoclasts - metabolism; Osteoclasts - pathology; Phagocytosis - physiology; Point Mutation; Rodents; Toll-Like Receptor 4 - drug effects; Toll-Like Receptor 4 - physiology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI71081

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.