Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
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.
当补体过度激活或失调时，它会成为感染与炎症病理学（包括牙周炎）之间的主要联系。这种口腔炎症性疾病与微生物群落失调有关，导致骨和其他支持牙齿的结构被破坏，并对全身健康产生不利影响。我们之前的研究表明，缺乏补体 C5a 受体（C5aR；CD88）或 TLR2 的小鼠对牙周炎具有高度且相似的抗性，这表明这两种受体之间可能存在相互作用参与了疾病过程。在本文中，我们证明 C5aR 和 TLR2 确实在牙周组织的炎症反应中协同作用，并揭示了一个新的药理学靶点来消除牙周炎。使用两种不同的牙周炎小鼠模型，我们表明局部使用 C5aR 拮抗剂可通过下调 TNF、IL-1β、IL-6 和 IL-17 来抑制牙周炎炎症，并进一步防止骨丢失，而与 TLR2 的存在与否无关。这些发现不仅揭示了 C5aR 和 TLR2 在牙周炎炎症中的关键合作，还为局部靶向 C5aR 作为治疗人类牙周炎的有力候选药物提供了概念验证。
