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(American Journal of Pathology. 2006;168:1189-1199.)
© 2006 American Society for Investigative Pathology

Protease-Activated Receptor-2 Activation

A Major Role in the Pathogenesis of Porphyromonas gingivalis Infection

Marinella Holzhausen^*, Luis Carlos Spolidorio, Richard P. Ellen, Marie-Claude Jobin, Martin Steinhoff, Patricia Andrade-Gordon^¶ and Nathalie Vergnolle^*

From the Department of Pharmacology and Therapeutics,^* Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Canadian Institute for Health Research Group in Matrix Dynamics and Dental Research Institute, University of Toronto, Toronto, Canada; the Department of Periodontology and Oral Pathology, Dental School of Araraquara, State University of São Paulo, Araraquara, São Paulo, Brazil; the Department of Dermatology, Ludwig Boltzman Institute for Immunobiology of the Skin, University Hospital, Muenster, Germany; and Drug Discovery,^¶ Johnson and Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania

We have investigated the specific contribution of protease-activated receptor-2 (PAR₂) to host defense during Porphyromonas gingivalis infection. Culture supernatants from P. gingivalis strains 33277 and W50 provoked Ca²⁺ mobilization in cells transfected with PAR₂ (PAR₂-KNRK) and desensitized the subsequent responses to PAR₂-selective agonist. In addition, culture supernatants of P. gingivalis E8 (RgpA/RgpB double knockout) did not cause calcium response in PAR₂-KNRK cells, evidencing the involvement of the arginine-specific cysteine proteases RgpA and RgpB in PAR₂ activation by P. gingivalis. Injection of P. gingivalis into mouse subcutaneous chambers provoked an increased proteolytic activity, which was inhibited by serine protease inhibitors. Fluids collected from chambers of P. gingivalis-injected mice were able to activate PAR₂ and this activation was inhibited by serine protease inhibitors. P. gingivalis inoculation into subcutaneous chambers of wild-type mice induced an inflammatory response that was inhibited by a serine protease inhibitor and was significantly reduced in PAR₂-deficient mice. Finally, mice orally challenged with P. gingivalis developed alveolar bone loss, which was significantly reduced in PAR₂-deficient mice at 42 and 60 days after P. gingivalis infection. We conclude that PAR₂ is activated on P. gingivalis infection, in which it plays an important role in the host inflammatory response.

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