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）是第二常见的口腔疾病，影响美国大约一半的成年人（6500万）。 美国的牙周炎导致牙齿脱落，并已牵连在几个严重的发病机制， 全身性疾病，包括糖尿病、心血管疾病和早产。牙周炎是一种慢性 炎症性疾病，由牙菌斑和牙石中存在的细菌感染引发;但实际疾病 表现是由宿主对这些病原体的免疫反应引起的。目前的标准治疗是 清创斑块和结石以减少细菌负荷;然而，没有治疗方法可以解决 PD的免疫成分因此，许多研究小组已经开始开发技术， 免疫反应和减少炎症。我们的团队专注于招募和极化M2 巨噬细胞作为牙周炎治疗的新途径。在我们之前的研究中，我们成功地阻止了 通过局部诱导小鼠牙周炎模型中的M2巨噬细胞的牙槽骨丢失。M2巨噬细胞 通过将C-C基序趋化因子2（CCL 2）释放PLGA微粒（MP）注射到牙周膜中来极化 组织中结果表明，通过局部递送CCL 2诱导M2巨噬细胞确实降低了M2巨噬细胞的增殖。 牙周炎的炎症和骨质流失。这项拟议的研究将进一步探索 M2巨噬细胞诱导CCL 2以及阐明这一过程的机制。我们 假设CCL 2在维持牙周免疫稳态中起关键作用，其外源性 传递，或基因消融，将通过牙周破坏，修复和 微生物群生态失调宏观经济在经济的破坏性和建设性阶段都发挥着重要作用。 通过调节它们进入M1（促炎/促破坏）的能力来调节炎症反应 或M2（抗炎/促修复）巨噬细胞。我们的假设得到了我们最近的研究的有力支持。 体内数据显示局部递送CCL 2将诱导巨噬细胞和单核细胞分化为 M2表型，从而导致牙周炎性骨丢失减少和牙周炎的发生。 修复.为了验证这一假设，我们提出了以下具体目标：1）测试CCL 2 MP作为干预性药物， 2）研究牙周炎患者的牙周表型、牙周破坏和修复情况， CCL 2-敲除小鼠（CCL 2-KO）;以及3）进行单细胞RNA测序（ScRNA-Seq）以获得 关于CCL 2的作用、其关联、对其他免疫系统的影响和相互作用的深入机制数据 细胞我们预计，从PLGA MP中释放的CCL 2将抑制进一步的骨丢失并促进骨修复。 小鼠牙周炎模型我们还期望CCL 2-KO小鼠和ScRNA-Seq分析将提供关键数据， 了解CCL 2免疫调节作用的潜在机制。因此，我们认为M2 CCL 2在炎症牙周组织中诱导巨噬细胞可能是治疗PD的一种新的、有前途的策略。