Enhanced TLR-MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism.

Abstract

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.

• Authors: Teruhito Yoshitaka, Tomoyuki Mukai, Mizuho Kittaka, Lisa M Alford, Salome Masrani, Shu Ishida, Ken Yamaguchi, Motohiko Yamada, Noriyoshi Mizuno, Bjorn R Olsen, Ernst J Reichenberger, Yasuyoshi Ueki
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 6 Pg. 1752-1766 (Sep 25 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25220465 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Intracellular Signaling Peptides and Proteins
• Myeloid Differentiation Factor 88
• NF-kappa B
• RNA, Messenger
• Sh3bp2 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse

Topics

• Adaptor Proteins, Signal Transducing (deficiency, genetics, metabolism)
• Animals
• Cells, Cultured
• Cherubism (etiology)
• Disease Models, Animal
• Inflammation
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, metabolism)
• Jaw (diagnostic imaging)
• Liver (pathology)
• Macrophages (cytology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (deficiency, genetics, metabolism)
• NF-kappa B (metabolism)
• Protein-Tyrosine Kinases (deficiency, genetics, metabolism)
• RNA, Messenger (metabolism)
• Radiography
• Signal Transduction
• Syk Kinase
• Toll-Like Receptor 2 (chemistry, metabolism)
• Toll-Like Receptor 4 (chemistry, metabolism)
• Tumor Necrosis Factor-alpha (blood, genetics, metabolism)