Titanium particle-induced inflammasome activation in the peri-implant mucosal barrier

Project Summary Peri-implantitis is an inflammatory disease of the oral mucosa and bone surrounding dental implants. Historically, this disease has been attributed to bacterial biofilms and the subsequent host inflammatory response, eliciting peri-implant tissue and jawbone destruction. However, recent findings indicate that release of titanium from implants may significantly contribute to the rampant inflammatory bone destruction observed in peri-implantitis. Data that support this contention include the lack of efficacy of antimicrobial treatments and a preponderance of the epidemiological evidence associating the presence of free titanium to ongoing peri- implant inflammation. A better understanding of immune responses to titanium in human disease can inform efforts to develop efficacious peri-implantitis therapeutic protocols. To date, there are no reliable peri- implantitis treatments to provide long-term resolution of peri-implant inflammation and jawbone destruction. This application will utilize a human-centered, clinical immunology model to investigate if titanium- induced inflammation can be reversed by inhibition of an intracellular protein assembly (known as, inflammasome) that amplifies inflammatory burden and regulates cell death. The proposed work will execute an in-depth investigation of the complex biological cascade that follows titanium microparticle dissolution from implants by coupling clinical data from a carefully selected human sample population with in vivo studies that exploit a knock-out mouse model of inflammasome inhibition. This study proposes two research aims: 1) assess NLRP3 Inflammasome Expression and Activation in Human Peri- implantitis, and 2) investigate the involvement of NLRP3-mediated pyroptosis in Titanium-related inflammation. The outcome of this work will determine if inflammasome activation in response to titanium implant-derived microparticles is central to peri-implant inflammation. The translational approach employs a preclinical mouse model that is based on the availability of mice that carry specific mutations that prevent inflammasome activation. Determining if inflammasome inhibition is a feasible molecular therapeutic target for titanium particle-mediated peri-implantitis will be the first critical step in identifying peri-implantitis therapeutic targets. The translational potential of this approach is supported by the availability of drugs that inhibit inflammasome activation and are currently assessed in clinical trials for other inflammatory conditions. Thus, the investigation of NLRP3 inhibition using a mouse model of tissue destruction and pathogenicity is innovative because it paves the way for molecular therapies of peri-implantitis that have the potential to be superior to the current antimicrobial treatments that demonstrate limited efficacy and high relapse rates. The continuation of this study will be pursued with a subsequent R01 application to conduct preclinical drug development for NLRP3 pathway modulation using peri-implantitis preclinical models and translation to human proof-of-principle. Ultimately this research will develop an optimal pharmacological strategy for resolving titanium-mediated peri-implantitis.