IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2

Asana Kamohara, Hirohito Hirata, Xianghe Xu, Makoto Shiraki, Sakuo Yamada, Jing Qi Zhang, Toshio Kukita, Kenji Toyonaga, Hiromitsu Hara, Yasuteru Urano, Yoshio Yamashita, Hiroshi Miyamoto, Akiko Kukita

Research output: Contribution to journalArticle

Abstract

Staphylococcus aureus is a main pathogen of osteomyelitis and protein A is a virulence factor with high affinity for IgG. In this study, we investigated whether S. aureus affects the differentiation and bone resorption of osteoclasts through the IgG-binding capacity of protein A. Staphylococcus aureus pre-treated with serum or IgG showed marked enhancement in osteoclastogenesis and bone resorption compared to non-treated S. aureus or a protein A-deficient mutant. Blocking of the Fc receptor and deletion of the Fcγreceptor gene in osteoclast precursor cells showed that enhanced osteoclastogenesis stimulated by S. aureus IgG immune complexes (ICs) was mediated by the Fc receptor on osteoclast precursor cells. In addition, osteoclastogenesis stimulated by S. aureus ICs but not the protein A-deficient mutant was markedly reduced in osteoclast precursor cells of Myd88-knockout mice. Moreover, NFATc1, Syk and NF-κB signals were necessary for osteoclastogenesis stimulated by S. aureus ICs. The results suggest the contribution of a of Toll-like receptor 2 (TLR2)-Myd88 signal to the activity of S. aureus ICs. We further examined the expression of pro-inflammatory cytokines that is known to be enhanced by FcγR-TLR cross-talk. Osteoclasts induced by S. aureus ICs showed higher expression of TNF-α and IL-1β, and marked stimulation of proton secretion of osteoclasts activated by pro-inflammatory cytokines. Finally, injection of S. aureus, but not the protein A-deficient mutant, exacerbated bone loss in implantation and intra-peritoneal administration mouse models. Our results provide a novel mechanistic aspect of bone loss induced by S. aureus in which ICs and both Fc receptors and TLR pathways are involved.

Original languageEnglish
Pages (from-to)89-104
Number of pages16
JournalInternational immunology
Volume32
Issue number2
DOIs
Publication statusPublished - Nov 12 2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Kamohara, A., Hirata, H., Xu, X., Shiraki, M., Yamada, S., Zhang, J. Q., Kukita, T., Toyonaga, K., Hara, H., Urano, Y., Yamashita, Y., Miyamoto, H., & Kukita, A. (2019). IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2. International immunology, 32(2), 89-104. https://doi.org/10.1093/intimm/dxz063