Calprotectin-mediated CD69 signaling in periodontitis

牙周炎中钙卫蛋白介导的 CD69 信号传导

• 批准号: 10298399
• 负责人: MASSIMO COSTALONGA
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298399
• 关键词: Acute; Adult; Affect; Animals; Binding; Cell Shape; Cells; Characteristics; Chronic; Chronic Phase; Complex; Data; Disease; Divalent Cations; Economics; Environment; Epithelial Cells; Etiology; Excision; Functional disorder; Gingiva; Human; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Innate Immune Response; Knockout Mice; Leucocytic infiltrate; Leukocyte L1 Antigen Complex; Ligands; Ligature; Mediating; Microbial Biofilms; Modeling; Names; Periodontal Diseases; Periodontitis; Periodontium; Phase; Porphyromonas gingivalis; Proteins; Recovery; Regulatory T-Lymphocyte; Reporting; Resolution; Role; S Phase; S100A8 gene; S100A9 gene; Signal Transduction; Stratified Squamous Epithelium; Structure of gingival sulcus; Testing; Therapeutic Intervention; Tissues; Tooth Loss; Tooth structure; alveolar bone; alveolar destruction; antimicrobial; bone; design; dysbiosis; fascinate; in vivo; intraepithelial; keratinocyte; microbial community; mouse model; neutrophil; novel; pathobiont; recruit; targeted treatment; tool

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.

7。项目摘要 /摘要 牙周炎是一种慢性炎症性疾病，其特征是牙周破坏，是 成人牙齿脱落的主要原因。它是由生物生物生物膜驱动的，该生物膜将牙龈沟定入。 我们试图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，据报道，CD69参与T调节细胞可诱导免疫抑制活性。一个 CD69介导的TREG激活的天然配体是钙蛋白钙蛋白酶素（CLP； S100A8与S100A9复合； S100A8； S100A8/A9; MRP8/14）。当在分层的鳞状上皮表达时，这种二价阳离子结合复合物 促进上皮内抗微生物防御。当被感染或取消释放时 但是，角质形成细胞或中性粒细胞，CLP可能与CD69+ T调节或T辅助17细胞相互作用，最终最终 抑制免疫反应。如果是这样，CLP可能在开始期间起作用 牙周炎与其假定的功能形成鲜明对比，作为促炎的“警报”。使用全局clp null鼠标， 我们的初步数据表明，CLP的净效应会抑制急性炎症性浸润的募集 并限制了结扎诱导的实验牙周炎模型中的牙周骨破坏。我们现在会 探索用卟啉牙（PG）引发的结扎诱导牙周炎的改良小鼠模型。 在解决阶段 我们假设在开始期间通过CD69信号 和分辨率阶段 实验 牙周炎症会抑制牙龈中的破坏性细胞浸润。为了检验我们的假设，我们 意志：1：表征最初归因于CLP的炎症细胞浸润的差异 和分辨率阶段 实验牙周炎。 2：确定PG培训的Treg细胞如何调节 通过CD69信号传导募集初始炎症细胞浸润 和CLP。 3：确定PG含有的Th17细胞对调节初始募集的贡献 和分辨率阶段 和分辨率阶段 炎症细胞浸润归因于CD69信号传导和CLP。向我们 知识，我们是第一个拥有数据的组，表明CLP会抑制A中的先天免疫反应 CD69依赖性方式。我们有工具来解释CLP如何促进先天免疫的招募 通过使用牙周炎的鼠模型在体内影响Treg和Th17细胞。最终，我们会的 表征Treg和Th17细胞中CLP和CD69信号传导如何塑造免疫细胞环境 牙龈驱动保护牙周组织或破坏肺泡骨。结果获得 这里将用于设计针对增强或抑制CLP活性的理论干预措施。批判的 将确定可能适合针对人类的治疗干预的步骤。最终我们 旨在减少牙周疾病的经济和个人燃烧。