Cherubism allele heterozygosity amplifies microbe-induced inflammatory responses in murine macrophages
Virginie Prod’Homme, Laurent Boyer, Nicholas Dubois, Aude Mallavialle, Patrick Munro, Xavier Mouska, Isabelle Coste, Robert Rottapel, Sophie Tartare-Deckert, Marcel Deckert
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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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 3

TLR4 signaling is impaired in macrophages from 3BP2-deficient and cherubic mice.

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TLR4 signaling is impaired in macrophages from 3BP2-deficient and cherub...
(A) Lysates from Sh3bp2WT/WT BMM were immunoprecipitated with protein G–sepharose beads coated with control Abs, anti-3BP2 Abs, or no Abs and immunoblotted using the indicated Abs. (B and C) Immunoblot analysis and (D) measurement of RAC activity by G-LISA were performed on cell lysates of BMM stimulated with LPS for the indicated times. (E) LPS-stimulated BMM were stained with fluorescent phalloidin and analyzed by flow cytometry (n = 3). Representative microscopic pictures of phalloidin and DAPI-stained BMM, either untreated (left) or stimulated with LPS for 30 minutes (right), are shown. (F) TNF-α was measured by ELISA in the serum of untreated mice (n = 6). (G) LPS was added for 28 days in mouse drinking water, and TNF-α in the serum was measured by ELISA (n = 6). P values were determined by the following tests: 2-way ANOVA (D, E and G); (Kruskal-Wallis test (F). *P < 0.05; **P < 0.01; ***P < 0.001.