Treatment of periodontitis by homing M2 macrophages

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PROJECT SUMMARY Periodontitis is the second most common oral disease, affecting about half of adults (65 millions) in the United States. Periodontitis causes tooth loss and has been implicated in several serious systemic diseases include diabetes, cardiovascular diseases, and immature birth. Periodontitis is a chronic inflammatory disease, triggered by bacterial infection present in dental plaques and calculus, but the disease itself is caused by host immune response to these pathogens. Current standard treatment is debridement of plaques and calculus to reduce the bacterial load, however, there are no therapies to address the immune aspect of the diseases. Thus, many research groups have started developing technologies to regulate the immune response and reduce inflammation. Our group has focused so far on recruiting T regulatory immune cells new target for therapy of periodontitis. In the previous study, we have successfully reduced alveolar bone loss by recruiting regulatory T cells in mouse and dog periodontitis model. Regulatory T cells were recruited by injecting C-C motif chemokine 22 (CCL22) releasing PLGA microparticles in the periodontal pockets. These results indicated that recruiting regulatory immune cells by local delivery of chemokine indeed reduces inflammation and bone loss in periodontitis. To further explore the principle of “recruitment of regulatory immune cells” and to continue our efforts to develop better therapies, we hypothesize that recruiting a larger population of anti-inflammatory immune cells such as M2 macrophages will achieve a better therapeutic option. Macrophages plays an important role in inflammatory responses, and interestingly have a polarization property by differentiating into M1 (pro- inflammatory) or M2 (anti-inflammatory) macrophages. Our hypothesis that is strongly supported by our recent in vivo pilot data is that the local delivery of CCL2 will induce homing of M2 macrophages, and differentiation of macrophages and monocytes to an M2 phenotype leading to decreased inflammation and bone loss in periodontal tissue. To test this hypothesis, we set the following specific aims; 1) To fabricate CCL2 releasing microparticles and analyze recruitment of M2 macrophage and differentiation of macrophages and monocytes to M2 macrophages and 2) To analyze effect of CCL2 on periodontitis in mouse model. We anticipate that CCL2 released from PLGA microparticles will recruit and induce M2 macrophages, and reduce inflammation and bone loss of periodontal tissue in mouse periodontitis model. Moreover, this concept could be applied to therapies for other inflammatory diseases such as delayed wound healing of diabetes or bowel disease.