Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist

J Immunol. 2012 Dec 1;189(11):5442-8. doi: 10.4049/jimmunol.1202339. Epub 2012 Oct 22.


When excessively activated or deregulated, complement becomes a major link between infection and inflammatory pathology including periodontitis. This oral inflammatory disease is associated with a dysbiotic microbiota, leads to the destruction of bone and other tooth-supporting structures, and exerts an adverse impact on systemic health. We have previously shown that mice deficient either in complement C5a receptor (C5aR; CD88) or TLR2 are highly and similarly resistant to periodontitis, suggesting that a cross-talk between the two receptors may be involved in the disease process. In this paper, we show that C5aR and TLR2 indeed synergize for maximal inflammatory responses in the periodontal tissue and uncover a novel pharmacological target to abrogate periodontitis. Using two different mouse models of periodontitis, we show that local treatments with a C5aR antagonist inhibited periodontal inflammation through downregulation of TNF, IL-1β, IL-6, and IL-17 and further protected against bone loss, regardless of the presence of TLR2. These findings not only reveal a crucial cooperation between C5aR and TLR2 in periodontal inflammation but also provide proof-of-concept for local targeting of C5aR as a powerful candidate for the treatment of human periodontitis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacteroidaceae Infections / drug therapy*
  • Bacteroidaceae Infections / immunology
  • Bacteroidaceae Infections / microbiology
  • Down-Regulation / drug effects
  • Drug Synergism
  • Gingiva / immunology
  • Immunity, Innate / drug effects
  • Injections
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / immunology
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / immunology
  • Lipopeptides / administration & dosage*
  • Mice
  • Peptides, Cyclic / administration & dosage*
  • Periodontitis / drug therapy*
  • Periodontitis / immunology
  • Periodontitis / microbiology
  • Porphyromonas gingivalis / drug effects*
  • Porphyromonas gingivalis / immunology
  • Receptor Cross-Talk / drug effects
  • Receptor Cross-Talk / immunology
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors*
  • Receptor, Anaphylatoxin C5a / metabolism
  • Toll-Like Receptor 2 / agonists
  • Toll-Like Receptor 2 / metabolism


  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-6
  • Lipopeptides
  • Pam(3)CSK(4) peptide
  • Peptides, Cyclic
  • Receptor, Anaphylatoxin C5a
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2