Treatment of Periodontitis by Homing M2 Macrophages

归巢 M2 巨噬细胞治疗牙周炎

基本信息

批准号：
10197100
负责人：
CHARLES SFEIR
金额：
$ 47.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10197100
关键词：
Ablation Address Adoptive Transfer Adult Affect Alveolar Bone Loss Anti-Inflammatory Agents Antibiotics Bacterial Infections Calculi Cardiovascular Diseases Cell Separation Cells Clinical Clinical Treatment Communities Data Debridement Dental Calculus Dental Plaque Diabetes Mellitus Disease Disease Progression Etiology Genetic Gingiva Harvest Helper-Inducer T-Lymphocyte Homeostasis Homing Immune Immune response Immune system Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-4 Intervention Knockout Mice Ligands Ligature Light Maxilla Methods Microbe Microbial Biofilms Modality Modeling Mouth Diseases Mus Nature Nutrient Pathogenesis Patients Periodicity Periodontal Diseases Periodontitis Periodontium Phase Phenotype Play Population Premature Birth Preventive therapy Process Public Health Rattus Reporting Research Resolution Role Severities Stains Sum System Systemic disease Technology Testing Therapeutic Therapeutic Effect Therapeutic Intervention Tissue Harvesting Tissues Tooth Loss Tooth structure Translating United States Wild Type Mouse aged bone loss chemokine chronic inflammatory disease cytokine dental biofilm dysbiosis experimental study feasibility testing immunoregulation in vivo inflammatory bone loss insight macrophage microCT microbial microbiota monocyte novel novel therapeutic intervention pathogen prevent recruit repaired response single-cell RNA sequencing standard care standard of care tumor-immune system interactions

项目摘要

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.

牙周炎（PD）是第二个最常见的口腔疾病，影响了约一半的成年人（6500万）美国牙周炎会导致牙齿脱落，并与全身性疾病，包括糖尿病，心血管疾病和牙周炎。炎症性疾病，是由牙斑和微积分中存在的双臂感染引起的；表现是由对这些病原体的宿主免疫反应引起的。斑块和微积分的清创术，以减少双臂载荷） PD的免疫成分。免疫反应并减少炎症。巨噬细胞作为牙周炎治疗的小噬细胞。通过局部诱导小鼠牙周炎模型中的M2巨噬细胞，肺泡骨质流失。通过注射C-C基序趋化因子2（CCL2）释放PLGA微粒（MPS）的极化组织。结果表明，通过局部递送CCL2诱导M2巨噬细胞牙周炎的炎症和骨质流失。 M2巨噬细胞诱导CCL2以及对过程的基础机理的启示假设CCL2在维持牙周免疫稳态中起关键作用，这是外源性的分娩或遗传消融将修改PD Throgh牙周分解，维修和巨噬细胞中的微生物群在破坏性和建设性阶段起着重要作用通过将极性调节为M1（促炎/促造成损害）来调节炎症反应或M2（抗炎/促欲庇护性）巨噬细胞。体内数据表明，CCL2的局部输送将诱导巨噬细胞和单核细胞的分化 M2表型，从而导致牙周炎症性骨质流失和牙周开始维修以检验此假设，我们证明以下特定目的：1）和修复牙周治疗； 2）研究牙周表型 CCL2敲除小鼠（CCL2-KO）和3）进行单细胞RNA测序（SCRNA-SEQ）有关CCL2的作用，其关联，效应效果的深度机械数据我们预计从PLGA MPS释放的CCL2将抑制进一步小鼠牙周炎模型。为了理解CCL2免疫调节作用的基本机制。 CCL2在发炎的牙周地区被CCL2杀害可能是一种新颖的治疗PD策略。