Calprotectin-mediated CD69 signaling in periodontitis

牙周炎中钙卫蛋白介导的 CD69 信号传导

基本信息

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
项目类别：
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

项目摘要

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. 项目概要/摘要牙周炎是一种以牙周组织破坏为特征的慢性炎症性疾病，成人牙齿脱落的主要原因是牙龈沟内的微生物生物膜失调。我们试图识别和表征对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 与 T 调节细胞的结合可诱导免疫抑制活性。 CD69 介导的 Tregs 激活的天然配体是钙卫蛋白（CLP；S100A8 与 S100A9 复合； S100A8/A9；MRP8/14) 当在复层鳞状上皮细胞中表达时，这种二价阳离子结合复合物当从感染或脱皮中释放时，似乎有助于上皮内抗菌防御。然而，CLP 最终可能与 CD69+ T 调节细胞或 T 辅助细胞 17 细胞相互作用如果是这样，CLP 可能在启动过程中发挥作用。牙周炎与其作为促炎“警报器”的假定功能相反，使用全局 CLP 缺失小鼠。我们的初步数据表明，CLP 的净效应抑制了急性炎症浸润的募集并限制结扎诱导的实验性牙周炎模型中的牙周骨破坏。探索用牙龈卟啉单胞菌 (Pg) 引发的结扎诱导牙周炎的改良小鼠模型。并在解决阶段我们见证了 CLP 在启动过程中通过 CD69 发出信号和解决阶段实验的牙周炎症可以抑制牙龈中的破坏性细胞浸润。为了检验我们的假设，我们进行了实验。将： 1：表征初始阶段 CLP 引起的炎症细胞浸润的差异和解决阶段实验性牙周炎 2：确定 Pg 引发的 Treg 细胞如何调节。通过 CD69 信号传导招募初始炎症细胞浸润和 CLP 3：确定 Pg 引发的 Th17 细胞对调节初始募集的贡献。和解决阶段和解决阶段 CD69 信号传导和 CLP 导致炎症细胞浸润。据了解，我们是第一组数据表明 CLP 会抑制先天免疫反应的研究组。我们有工具来解释 CLP 如何促进先天免疫的募集。最终，我们将通过使用小鼠牙周炎模型来影响体内的 Treg 和 Th17 细胞。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驱动保护牙周组织或破坏牙槽骨所获得的结果。这里将用于设计旨在增强或抑制 CLP 活性的治疗干预措施。最终我们将确定可能适合人类针对性治疗干预的步骤。旨在减轻牙周病的经济和个人负担。