Calprotectin-mediated CD69 signaling in periodontitis

7.项目摘要/摘要 牙周炎是一种慢性炎症性疾病，其特征是牙周组织遭到破坏。 成人牙齿脱落的主要原因。它是由一种生长在牙龈沟中的非生物微生物膜驱动的。 我们寻求识别和表征导致牙周炎的微生物生物膜的局部免疫反应。 最近，CD69与T调节细胞的结合被报道可诱导免疫抑制活性。一个 CD69介导的Treg活化的天然配体是钙保护素(CLP；S100A8与S100A9络合； S100A8/A9；MRP8/14)。当在复层鳞状上皮中表达时，这种二价阳离子结合复合体 似乎有助于上皮内的抗菌防御。当从感染或脱皮中释放时 然而，角质形成细胞或中性粒细胞，CLP可能最终与CD69 T调节细胞或T辅助17细胞相互作用 抑制免疫反应。如果是这样的话，中电可以在启动 牙周炎与其作为促炎“警报器”的假定功能相反。使用全局CLP空鼠标， 我们的初步数据表明，CLP的净效应抑制了急性炎症浸润物的招募 并在结扎诱导的实验性牙周炎模型中限制牙周骨的破坏。我们现在就会 探索牙龈卟啉单胞菌(PG)诱导的小鼠牙周炎模型。 并且在解决阶段 我们推测CLP在启动过程中通过CD69发出信号 和解决阶段 试验性的 牙周炎能抑制细胞在牙周组织中的破坏性渗透。为了检验我们的假设，我们 Will：1：描述CLP发病初期炎性细胞浸润的不同 和解决阶段 实验性牙周炎。2：确定PG诱导的Treg细胞是如何调节的 CD69信号途径对初始炎性细胞的募集 和中电。3：确定PG诱导的Th17细胞在调节初始 和解决阶段 和解决阶段 CD69信号转导和CLP引起的炎性细胞浸润。致我们的 知识，我们是第一个有数据表明CLP抑制先天免疫反应的小组 CD69依赖方式。我们有工具来解释CLP如何促进先天免疫的招募 通过使用牙周炎小鼠模型在体内影响Treg和Th17细胞。最终，我们会 描述Treg和Th17细胞中的CLP和CD69信号如何塑造免疫细胞环境 牙龈可以保护牙周组织，也可以破坏牙槽骨。所获得的结果 这里将被用来设计旨在促进或抑制CLP活性的治疗性干预。批判性 将确定可能适用于人类靶向治疗干预的步骤。最终我们 目的减轻牙周病的经济和个人负担。

7. PROJECT SUMMARY / ABSTRACT Periodontitis is a chronic inflammatory condition characterized by the destruction of the periodontium and is the leading cause of tooth loss in adults. It is driven by a dysbiotic microbial biofilm that colonizes the gingival sulcus. We seek to identify and characterize the local immune response to the microbial biofilm that leads to periodontitis. Recently, CD69 engagement on T regulatory cells was reported to induce immunosuppressive activities. A natural ligand for CD69-mediated activation of Tregs is calprotectin (CLP; S100A8 complexed to S100A9; S100A8/A9; MRP8/14). When expressed in stratified squamous epithelia, this divalent cation-binding complex appears to contribute to intraepithelial antimicrobial defense. When released from infected or desquamating keratinocytes or neutrophils, however, CLP may interact with CD69+ T regulatory or T helper 17 cells, ultimately suppressing the immune response. If so, CLP may function during the initiation of periodontitis contrary to its postulated function as a proinflammatory “alarmin”. Using a global CLP null mouse, our preliminary data suggest that the net effect of CLP dampens the recruitment of an acute inflammatory infiltrate and limits periodontal bone destruction in a ligature-induced experimental periodontitis model. We will now explore a modified mouse model of ligature-induced periodontitis primed with Porphyromonas gingivalis (Pg). and in the resolution phase We hypothesize that CLP signals through CD69 during the initiation and resolution phases of experimental periodontal inflammation to dampen the destructive cellular infiltrate in the gingiva. To test our hypothesis, we will: 1: Characterize the differences in the inflammatory cell infiltrate attributable to CLP during the initial and resolution phases of experimental periodontitis. 2: Determine how Pg-primed Treg cells modulate the recruitment of the initial inflammatory cell infiltrates through CD69 signaling and CLP. 3: Determine the contribution of Pg-primed Th17 cells to modulating recruitment of the initial and resolution phase and resolution phase inflammatory cell infiltrates attributable to CD69 signaling and CLP. To our knowledge, we are the first group with data suggesting that CLP dampens the innate immune response in a CD69-dependent manner. We have the tools to explain how CLP contributes to recruitment of innate immune cells by affecting Treg and Th17 cells in vivo using a murine model of periodontitis. Ultimately, we will characterize how CLP and CD69 signaling in Treg and Th17 cells shapes the immune cell environment in the gingiva to drives either protection of periodontal tissues or destruction of alveolar bone. The results obtained here will be used to design therapeutic interventions directed at boosting or inhibiting the activity of CLP. Critical steps will be identified that might be amenable to targeted therapeutic intervention in humans. Ultimately we aim to reduce the economic and personal burden of periodontal diseases.