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

• 批准号: 10353423
• 负责人: MASSIMO COSTALONGA
• 金额: $ 19.38万
• 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: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353423
• 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

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。项目摘要 /摘要 牙周炎是一种普遍的慢性炎症疾病，其特征是破坏牙周 最终导致成人牙齿脱落。它是由不创伤生物生物膜驱动的，该生物膜定居 牙齿周围的牙龈沟。我们试图识别和表征对失调的局部免疫反应 导致牙周炎的生物膜。最近，据报道CD69参与调节T细胞以诱导 免疫抑制活动。 CD69介导的调节T细胞激活的天然配体是 Calprotectin（S100A8与S100A9复合； S100A8/A9）。当在分层的鳞状上皮表达时， 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，当从中性粒细胞释放或被感染或脱离角质形成细胞时，钙蛋白钙蛋白酶素可能相互作用 使用CD69+ T调节或T辅助器17个细胞，最终抑制免疫响应。如果是这样，钙骨蛋白 在牙周炎开始期间，可能会抑制功能与其张贴的作用形成对比 促炎的“警报”。我们使用全局钙骨蛋白null鼠标，我们的初步数据表明网络 钙骨蛋白的作用会抑制急性炎症性浸润和牙周骨的募集 结扎诱导的实验牙周炎模型中的破坏。我们现在将探索一种新颖的鼠模型 结扎诱导的牙周炎，用牙龈卟啉单胞菌（PG）毒牙引发。我们假设这一点 在实验牙周注射倡议期间，通过CD69通过CD69信号抑制A 破坏性细胞浸润到牙龈。为了检验我们的假设，我们将：1：表征差异 在实验性牙周炎的初始阶段，在炎症细胞中浸润 钙骨蛋白。 2。确定CD69信号对初始募集的贡献 在存在和不存在钙染色素的情况下，炎性细胞浸润。据我们所知，我们是 第一组具有数据表明钙粘蛋白会抑制先天免疫反应。我们有工具 解释钙骨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 CD69在体内信号传导使用牙周炎的鼠模型。我们将表征calprotectin和cd69 Treg细胞中的信号传导塑造了其他效应T细胞上的免疫抑制。最终，我们将阐明 Gingiva中通过CD69全局信号传导的钙骨蛋白是否驱动牙周组织的保护或 肺泡骨的破坏。此处获得的结果将用于设计理论干预措施 致力于促进或抑制钙染色素的活性。将确定可能是 适合针对人类的有针对性的治疗干预，以减少经济和个人 牙周炎负担。