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Calprotectin and CD69 affect regulatory T cell responses in periodontal disease

钙卫蛋白和 CD69 影响牙周病中调节性 T 细胞反应

基本信息

批准号：
10217424
负责人：
MASSIMO COSTALONGA
金额：
$ 23.21万
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：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217424
关键词：
Acute Adult Affect Binding Calcium Cell Shape Cells Chronic Complex Data Disease Divalent Cations Economics Environment Epithelial Cells Gingiva Human Immune Immune response Immunosuppression Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Innate Immune Response Interleukin-17 Knockout Mice Leucocytic infiltrate Leukocyte L1 Antigen Complex Ligands Ligature Manganese Mediating Microbial Biofilms Modeling Periodontal Diseases Periodontitis Periodontium Porphyromonas gingivalis Proteins Regulatory T-Lymphocyte Reporting Role S100A8 gene S100A9 gene Shapes Signal Transduction Stratified Squamous Epithelium Structure of gingival sulcus T cell response Testing Therapeutic Intervention Tissues Tooth Loss Tooth structure alveolar bone alveolar destruction antimicrobial bone design dysbiosis effector T cell 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 prevalent chronic inflammatory condition characterized by the destruction of the periodontium that ultimately leads to tooth loss in adults. It is driven by a dysbiotic microbial biofilm that colonizes the gingival sulcus around teeth. We seek to identify and characterize the local immune response to the dysbiotic biofilm that leads to periodontitis. Recently, CD69 engagement on regulatory T cells was reported to induce immunosuppressive activities. A natural ligand for CD69-mediated activation of regulatory T cells is calprotectin (S100A8 complexed to S100A9; S100A8/A9). When expressed in stratified squamous epithelia, this divalent cation-binding heterodimeric complex appears to contribute to intraepithelial antimicrobial defense. When released from neutrophils or infected or desquamating keratinocytes, however, calprotectin may interact with CD69+ T regulatory or T helper 17 cells, ultimately suppressing the immune response. If so, calprotectin may suppressive functions during the initiation of periodontitis contrary to its postulated role as a proinflammatory “alarmin”. Using a global calprotectin null mouse, our preliminary data suggest that the net effect of calprotectin 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 novel murine model of ligature-induced periodontitis primed with Porphyromonas gingivalis (Pg) gavage. We hypothesize that calprotectin signals through CD69 during the initiation of experimental periodontal inflammation to dampen a destructive cellular infiltrate into the gingiva. To test our hypothesis, we will: 1: Characterize the differences in the inflammatory cell infiltrate during the initial stage of experimental periodontitis attributable to calprotectin. 2. Determine the contribution of CD69 signaling to the recruitment of the initial inflammatory cell infiltrate in the presence and absence of calprotectin. To our knowledge, we are the first group with data suggesting that calprotectin dampens the innate immune response. We have the tools to explain how calprotectin contributes to recruitment of innate immune cells in the gingiva by affecting global CD69 signaling in vivo using a murine model of periodontitis. We will characterize how calprotectin and CD69 signaling in Treg cells shapes immunosuppression on other effector T cells. Ultimately, we will elucidate whether calprotectin via CD69 global signaling in the gingiva 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 calprotectin. Critical steps will be identified that might be amenable to targeted therapeutic intervention in humans aiming at reducing the economic and personal burden of periodontitis.

7. 项目概要/摘要牙周炎是一种常见的慢性炎症性疾病，其特征是牙周组织的破坏最终导致成年人牙齿脱落。它是由定植于细胞内的失调微生物生物膜驱动的。牙齿周围的牙龈沟。我们寻求识别和表征对菌群失调的局部免疫反应导致牙周炎的生物膜。最近，据报道 CD69 与调节性 T 细胞的结合可诱导免疫抑制活性。 CD69 介导的调节性 T 细胞激活的天然配体是钙卫蛋白（S100A8 与 S100A9 复合；S100A8/A9）。当在复层鳞状上皮中表达时，这种二价阳离子结合异二聚体复合物似乎有助于上皮内抗菌防御。然而，当中性粒细胞或感染或脱落的角质形成细胞释放时，钙卫蛋白可能会相互作用与 CD69+ T 调节性或 T 辅助 17 细胞结合，最终抑制免疫反应。如果是这样，钙卫蛋白在牙周炎发生过程中可能会发挥抑制作用，这与其作为牙周炎的假定作用相反。促炎“警报素”。使用全局钙卫蛋白无效小鼠，我们的初步数据表明网络钙卫蛋白的作用抑制急性炎症浸润的募集并限制牙周骨结扎诱导的实验性牙周炎模型中的破坏。我们现在将探索一种新颖的小鼠模型用牙龈卟啉单胞菌 (Pg) 灌胃引发结扎诱发的牙周炎。我们假设在实验性牙周炎症启动过程中，钙卫蛋白通过 CD69 发出信号来抑制破坏性细胞浸润到牙龈。为了检验我们的假设，我们将： 1：描述差异的特征在实验性牙周炎的初始阶段，炎症细胞浸润可归因于钙卫蛋白。 2. 确定 CD69 信号对初始招募的贡献在钙卫蛋白存在和不存在的情况下炎症细胞浸润。据我们所知，我们是第一组数据表明钙卫蛋白会抑制先天免疫反应。我们有工具解释钙卫蛋白如何通过影响全局来促进牙龈中先天免疫细胞的募集使用小鼠牙周炎模型进行体内 CD69 信号传导。我们将描述钙卫蛋白和 CD69 如何 Treg 细胞中的信号传导会影响其他效应 T 细胞的免疫抑制。最终我们将阐明钙卫蛋白是否通过牙龈中的 CD69 全局信号传导来驱动牙周组织的保护或牙槽骨的破坏。这里获得的结果将用于设计治疗干预措施旨在增强或抑制钙卫蛋白的活性。将确定可能的关键步骤适合对人类进行有针对性的治疗干预，旨在减少经济和个人损失牙周炎的负担。