Periodontitis (PD) 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 the pathogenesis of several serious systemic diseases including diabetes, cardiovascular diseases, and premature birth. Periodontitis is a chronic inflammatory disease, triggered by bacterial infection present in dental plaques and calculus; but actual disease manifestations are 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 that address the immune component of PD. Thus, many research groups have started developing technologies to regulate the immune response and reduce inflammation. Our group has focused on recruiting and polarizing M2 macrophage as novel approaches for therapy of periodontitis. In our previous study, we successfully prevented alveolar bone loss by locally inducing M2 macrophages in mouse periodontitis models. M2 macrophages were polarized by injecting C-C motif chemokine 2 (CCL2) releasing PLGA microparticles (MPs) into periodontal tissues. The results indicated that inducing M2 macrophages by local delivery of CCL2 indeed reduces inflammation and bone loss in periodontitis. The proposed study will explore further the therapeutic potential of M2 macrophage induction by CCL2 as well as shed light on the mechanism underlying this process. We hypothesize that CCL2 plays a key role in maintaining periodontal immune homeostasis, and that its exogenous delivery, or genetic ablation, would modify the course of PD through periodontal breakdown, repair and microbiota dysbiosis. Macrophages play an important role in both the destructive and constructive phases of the inflammatory response by modulating their ability to polarize into either M1 (pro-inflammatory/pro-destructive) or M2 (anti-inflammatory/pro-reparative) macrophages. Our hypothesis is strongly supported by our recent in vivo data showing that the local delivery of CCL2 will induce differentiation of macrophages and monocytes to an M2 phenotype, thus leading to decreased periodontal inflammatory bone loss and initiation of periodontal repair. To test this hypothesis, we propose the following specific aims: 1) To test CCL2 MPs as an interventional and reparative periodontal therapy; 2) To study the periodontal phenotype, periodontal breakdown and repair in CCL2-knockout mice (CCL2-KO); and 3) To perform Single cell RNA sequencing (ScRNA-Seq) to acquire in- depth mechanistic data about the role of CCL2, its association, effect on and interactions with other immune cells. We anticipate that CCL2 released from PLGA MPs will inhibit further bone loss and promote repair in the mouse periodontitis model. We also expect that CCL2-KO mice and ScRNA-Seq analysis will provide data critical to understanding underlying mechanisms of CCL2?s immunoregulatory effects. In sum, we believe that M2 macrophage induction by CCL2 in inflamed periodontium could be a novel, promising strategy for treating PD.
This study is relevant to the public health because large population (half of adult population) is affected by periodontitis, and the methods used in this study can be easily translated to noninvasive clinical treatment. In addition, this study will establish the efficacy of recruiting and differentiating macrophages to M2 macrophages which could also be used as a treatment to other chronic inflammatory diseases.
