IL-22, Immune Plasticity, and Autotherapy in the Periodontium

项目摘要 稳健性是指系统在抵御内部或外部干扰时保持其功能的能力，并且 由可塑性机制实现，这是免疫系统等生物系统的一大特点。 自体疗法是优化内源性组织反应的方法，以维持健康、治疗疾病和 增强组织修复，在很大程度上是通过恢复生物健壮性。白介素22介导的单向性 从免疫细胞到组织基质细胞的通讯和促进动态平衡免疫，干细胞功能 和组织再生。然而，IL-22在慢性阻塞性肺疾病中既与有害活动有关，也与保护活动有关 炎症性疾病，这混淆了其作为治疗靶点的潜力。这样做的总体目标是 建议明确定义IL-22在牙周病(PD)中的功能，并获得上下文依赖的 了解其保护或破坏潜力，将使IL-22靶向自体疗法能够促进 牙周组织中的免疫健壮性。总体假设是，IL-22的作用依赖于上下文 这会影响组织的可塑性，从执行免疫监测或抗击感染的组织到 适合再生的。具体地说，IL-22被认为通过(I)调节牙周组织的免疫可塑性 在稳定状态下保持组织完整性(在目标1中检查)，有助于强劲的免疫反应 在PD期间变得具有破坏性(目标2)，并在分辨率中充当骨再生的效应器 阶段(目标3)。在目标1中，设计了体内干预研究，以探索对IL-22的需求。 牙周组织稳态。Aim 2通过体外和体内机制检查 实验中，假设IL-22与IL-17协同作用，IL-17是一种促炎细胞因子，在 帕金森病，在帕金森病诱导期促进破坏性炎症。目标3探索了这样的假设 IL-22在PD缓解期促进炎症清除和骨再生，当 IL-17的表达显著下降。关于IL-22促进成骨的机制，它 将研究IL-22是否促进间充质干细胞的增殖和成骨分化 细胞。拟议的研究有望导致对生物学的依赖于上下文的理解 白介素22在帕金森病中的作用，导致以白介素22为靶点的新的自身疗法，以适当地调节免疫 恢复牙周组织的可塑性和动态平衡，从而使帕金森病患者受益。

Project Summary Robustness is the ability of a system to maintain its functionality against internal or external perturbations and is enabled by mechanisms of plasticity, a major feature of biological systems such as the immune system. Autotherapies are approaches to optimize endogenous tissue responses to maintain health, treat diseases and enhance tissue repair, in great part by restoring biological robustness. Interleukin (IL)-22 mediates unidirectional communication from immune cells to tissue stromal cells and promotes homeostatic immunity, stem cell function and tissue regeneration. However, IL-22 is associated with both detrimental and protective activities in chronic inflammatory disorders, which has confounded its potential as a therapeutic target. The overall objective of this proposal is to clearly define the functions of IL-22 in periodontal disease (PD) and attain a context-dependent understanding of its protective or destructive potential, which will enable IL-22-targeted autotherapies to promote immune robustness in the periodontium. The overall hypothesis is that IL-22 acts in a context-dependent manner that influences the plasticity of the tissue from one tailored to perform immune surveillance or fight infections, to one fitted for regeneration. Specifically, IL-22 is proposed to regulate periodontal tissue immune plasticity by (i) preserving tissue integrity during steady-state (examined in Aim 1), contributing to vigorous immune responses that become destructive during PD (Aim 2), and acting as an effector of bone regeneration in the resolution phase (Aim 3). In Aim 1, in vivo intervention studies were designed to explore the requirement for IL-22 in periodontal tissue homeostasis at steady state. Aim 2 examines, through both in vitro and in vivo mechanistic experiments, the hypothesis that IL-22 synergizes with IL-17, a proinflammatory cytokine that is upregulated in PD, to promote destructive inflammation during the inductive phase of PD. Aim 3 explores the hypothesis that IL-22 promotes inflammation clearance and bone regeneration during the resolution phase of PD, when the expression of IL-17 massively declines. Regarding the mechanism by which IL-22 can promote osteogenesis, it will be investigated whether IL-22 promotes the proliferation and osteogenic differentiation of mesenchymal stem cells. The proposed studies are expected to lead to a context-dependent understanding of the biological functions of IL-22 in PD, leading to novel IL-22-targeted autotherapies to appropriately modulate immune plasticity and restore homeostasis in the periodontium, thereby benefiting PD patients.