Treatment of Periodontitis by Homing M2 Macrophages

归巢 M2 巨噬细胞治疗牙周炎

• 批准号: 10649608
• 负责人: CHARLES SFEIR
• 金额: $ 47.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10649608
• 关键词: Ablation; Acceleration; 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; Macrophage; Maxilla; Methods; Microbe; Microbial Biofilms; Modality; Modeling; Mouth Diseases; Mus; Nature; Nutrient; Pathogenesis; Patients; Periodicals; Periodontal Diseases; Periodontitis; Periodontium; Phase; Phenotype; Play; Population; Premature Birth; Preventive therapy; Process; Public Health; Rattus; Reporting; Research; Resolution; Role; Severities; Stains; 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; microCT; microbial; microbiota; monocyte; novel; novel therapeutic intervention; particle; particle therapy; pathogen; prevent; recruit; repaired; response; single-cell RNA sequencing; standard care; standard of care; tumor-immune system interactions

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，并在几种严重的发病机理中暗示 全身性疾病，包括糖尿病，心血管疾病和早产。牙周炎是慢性 炎症性疾病，是由牙菌斑和微积分中存在的细菌感染引起的；但是实际疾病 表现是由对这些病原体的免疫反应引起的。当前的标准治疗是 斑块和计算的清创术，以减少细菌负荷；但是，没有疗法可以解决 PD的免疫成分。这是许多研究小组开始开发以规范的技术 免疫反应并减少炎症。我们的小组专注于招募和两极分化M2 巨噬细胞作为牙周炎治疗的新方法。在我们先前的研究中，我们成功地阻止了 小鼠牙周炎模型中局部诱导的M2巨噬细胞的肺泡骨质流失。 M2巨噬细胞是 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诱导的M2巨噬细胞确实减少了 牙周炎的炎症和骨质流失。拟议的研究将进一步探讨 CCL2的M2巨噬细胞诱导以及对此过程的基础机制的启示。我们 假设CCL2在维持牙周免疫稳态中起关键作用，并且其外源性 分娩或遗传消融将通过牙周分解，维修和 微生物群营养不良。巨噬细胞在破坏性和建设性阶段都起着重要作用 炎症反应通过调节其两极分化成M1的能力（促炎/促造成损害） 或M2（抗炎/促育）巨噬细胞。我们最近的假设得到了我们最近的强烈支持 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。为了检验该假设，我们提出以下特定目的：1）测试CCL2 MP作为介入 和修复牙周治疗； 2）研究牙周表型，牙周分解和修复 CCL2-KNOCKOUT小鼠（CCL2-KO）; 3）执行单细胞RNA测序（SCRNA-SEQ）以获取内部 关于CCL2的作用，其关联，对其他免疫的效果和相互作用的深度机械数据 细胞。我们预计从PLGA MPS释放的CCL2将抑制进一步的骨质流失并促进修复 小鼠牙周炎模型。我们还期望CCL2-KO小鼠和SCRNA-SEQ分析将提供关键的数据 了解CCL2免疫调节作用的潜在机制。总而言之，我们相信M2 CCL2在发炎的牙周地区诱导巨噬细胞可能是治疗PD的新型策略。