Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages
Virginie Prod’Homme, … , Sophie Tartare-Deckert, Marcel Deckert
Virginie Prod’Homme, … , Sophie Tartare-Deckert, Marcel Deckert
Published February 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1396-1400. https://doi.org/10.1172/JCI71081.
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Brief Report Immunology

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

Virginie Prod’Homme, Laurent Boyer, Nicholas Dubois, Aude Mallavialle, Patrick Munro, Xavier Mouska, Isabelle Coste, Robert Rottapel, Sophie Tartare-Deckert, Marcel Deckert

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Figure 2

Macrophages from 3BP2-deficient and cherubic mice display impaired phagocytosis.

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Macrophages from 3BP2-deficient and cherubic mice display impaired phago...
BMM were incubated 10 minutes with E. coli–FITC (n = 5) (A) or Ab-opsonized E. coli–FITC (n = 5) (B), and intracellular fluorescence was analyzed by flow cytometry. (C) 107 E. coli bacteria were injected in the mouse tail veins. Blood samples were harvested 3, 6, 24, and 48 hours after injection, and the number of bacteria per ml of blood was counted after 16 hours culture on LB-agar (n = 14). (D) BMM were incubated 10 minutes with E. coli–FITC (n = 3), and intracellular fluorescence was analyzed by flow cytometry. (E) BMM were incubated with latex fluorescent beads (n = 4). Cytochalasin B (CytB) was added to inhibit phagocytosis in control wells. P values were determined by the following tests: 2-tailed Mann-Whitney U test (A and B); 2-way ANOVA (C–E). *P < 0.05; **P < 0.01.