Enhanced TLR-MYD88 Signaling Stimulates Autoinflammation in SH3BP2 Cherubism Mice and Defines the Etiology of Cherubism

• Published in: Cell reports (Cambridge) Vol. 8; no. 6; pp. 1752 - 1766
• Main Authors: Yoshitaka, Teruhito, Mukai, Tomoyuki, Kittaka, Mizuho, Alford, Lisa M., Masrani, Salome, Ishida, Shu, Yamaguchi, Ken, Yamada, Motohiko, Mizuno, Noriyoshi, Olsen, Bjorn R., Reichenberger, Ernst J., Ueki, Yasuyoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2014; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cells, Cultured; Cherubism - etiology; Disease Models, Animal; Inflammation; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Jaw - diagnostic imaging; Liver - pathology; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88 - deficiency; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - metabolism; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Radiography; RNA, Messenger - metabolism; Signal Transduction; Syk Kinase; Toll-Like Receptor 2 - chemistry; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - chemistry; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.08.023

Cherubism is caused by mutations in SH3BP2. Studies of cherubism mice showed that tumor necrosis factor α (TNF-α)-dependent autoinflammation is a major cause of the disorder but failed to explain why human cherubism lesions are restricted to jaws and regress after puberty. We demonstrate that the inflammation in cherubism mice is MYD88 dependent and is rescued in the absence of TLR2 and TLR4. However, germ-free cherubism mice also develop inflammation. Mutant macrophages are hyperresponsive to PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) that activate Toll-like receptors (TLRs), resulting in TNF-α overproduction. Phosphorylation of SH3BP2 at Y183 is critical for the TNF-α production. Finally, SYK depletion in macrophages prevents the inflammation. These data suggest that the presence of a large amount of TLR ligands, presumably oral bacteria and DAMPs during jawbone remodeling, may cause the jaw-specific development of human cherubism lesions. Reduced levels of DAMPs after stabilization of jaw remodeling may contribute to the age-dependent regression. [Display omitted] •TLR2/4-MYD88 signaling controls TNF-α-dependent autoinflammation in cherubism mice•Cherubism inflammation occurs even in a germ-free environment•Cherubism mutation enhances macrophage responsiveness to PAMP/DAMP ligands for TLRs•SYK may be a potential therapeutic target for the treatment of cherubism The jaw shows a distinct phenotype in human cherubism that disappears with age. Yoshitaka et al. now address this mysterious disease progression by studying the mechanism of inflammation in a mouse cherubism model. Absence of TLR2/TLR4 rescues the mice from inflammation. However, the inflammation occurs even in the absence of microorganisms. These results suggest that both abundant oral bacteria and active jaw remodeling are the cause of jaw-specific lesions and that later stabilization of jaw remodeling might explain the age-dependent effects of this disease.