Protease-Activated Receptor 2 Has Pivotal Roles in Cellular Mechanisms Involved in Experimental Periodontitis

Abstract

The tissue destruction seen in chronic periodontitis is commonly accepted to involve extensive upregulation of the host inflammatory response. Protease-activated receptor 2 (PAR-2)-null mice infected with Porphyromonas gingivalis did not display periodontal bone resorption in contrast to wild-type-infected and PAR-1-nullinfected mice. Histological examination of tissues confirmed the lowered bone resorption in PAR-2-null mice and identified a substantial decrease in mast cells infiltrating the periodontal tissues of these mice. T cells from P. gingivalis-infected or immunized PAR-2-null mice proliferated less in response to antigen than those from wild-type animals. CD90 (Thy1.2) expression on CD4؉ and CD8 ؉ T-cell-receptor ␤ (TCR␤) T cells was significantly (P < 0.001) decreased in antigen-immunized PAR-2-null mice compared to sham-immunized PAR-2-null mice; this was not observed in wild-type controls. T cells from infected or antigen-immunized PAR-2-null mice had a significantly different Th1/inflammatory cytokine profile from wild-type cells: in particular, gamma interferon, interleukins (interleukin-2, -3, and -17), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha demonstrated lower expression than wild-type controls. The absence of PAR-2 therefore appears to substantially decrease T-cell activation and the Th1/inflammatory response. Regulation of such proinflammatory mechanisms in T cells and mast cells by PAR-2 suggests a pivotal role in the pathogenesis of the disease.

Novel agonists & antagonists for protease-activated receptor 2 and C3a receptor

“…Antagonists AY117 (167) and AY265 (192) were able to inhibit intracellular calcium release in HT29 cells stimulated by PAR2 agonists, 2f-LIGRLO-NH 2 or endogenous trypsin, and blocked the release of pro-inflammatory cytokines (IL6, TNF-α) in primary human tubule epithelial cells (HTEC). They were also generally more stable than LL13C (133) and LL115 (159) in rat liver homogenate. AY117 (167) was orally bioavailable and effective for the treatment of joint inflammation in rats at 10 mg/kg dose.…”

Porphyromonas gingivalis gingipains induce a pro-inflammatory extracellular microenvironment : the role of PAR-2 and fibronectin.

“…One example, oral challenge with a PAR-2 agonist not only increased existing periodontitis in rats, but also caused the development of the disease with the clinical hall marks of alveolar bone loss, gingival granulocyte infiltration accompanied by the overexpression of matrix metalloproteinase (MMP)-2, MMP-9, cyclooxygenase 1 and cyclooxygenase 2 [91]. Furthermore, Wong and team demonstrated PAR-2 knockout mice orally infected with P. gingivalis showed significantly reduced or no alveolar bone loss when compared to wild-type or PAR-1 knockout P. gingivalis infected mice [92]. The lack of alveolar bone loss in the PAR-2 knockout mice was followed by a large decrease in the infiltration of mast cells and type 1 helper T-cell dependent cytokines, such as interleukin-2 and interleukin-17 and TNFalpha [92].…”

“…Furthermore, Wong and team demonstrated PAR-2 knockout mice orally infected with P. gingivalis showed significantly reduced or no alveolar bone loss when compared to wild-type or PAR-1 knockout P. gingivalis infected mice [92]. The lack of alveolar bone loss in the PAR-2 knockout mice was followed by a large decrease in the infiltration of mast cells and type 1 helper T-cell dependent cytokines, such as interleukin-2 and interleukin-17 and TNFalpha [92]. Considering these studies, there is no doubt about the important role PAR-2 plays in periodontal disease.…”

“…The mast cells could release tryptase, which can additionally activate PAR-2. Furthermore, mast cells can release TNF-alpha further adding to the inflammatory milieu [92]. Lastly, neutrophil infiltration would lead to the increase of proteinase-3, which also is known to activate PAR-2 [92,93].…”

“…The first layer of PAR-2 activation is completed by the arginine specific gingipains. As discussed above, this leads to the expression of inflammatory cytokines, such as interleukin-6, that directly enhances bone resporption via osteoclasts [77,92]. Another layer we need to consider is mast cells, which also recognize P. gingivalis.…”