SGK1 and the control of periodontal inflammation

SGK1 与牙周炎症的控制

基本信息

批准号：
9988663
负责人：
Huizhi Wang
金额：
$ 36.87万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-21 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9988663
关键词：
Acute Adopted Agonist Alveolar Bone Loss Anti-Inflammatory Agents Anti-inflammatory Autocrine Communication Bacteria Biological Response Modifiers Bone Resorption Cells Chronic Communities Coronary Arteriosclerosis Data Development Disease Ensure Equilibrium Gingiva Glucocorticoids Goals Gram-Negative Bacteria Homeostasis Human IL8 gene Immune Immune response Immunomodulators In Vitro Infection Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 beta Interleukin-10 Interleukin-12 Interleukin-6 Investigation Knockout Mice MAP3K7 gene MAPK phosphatase Mediating Modeling Modification Molecular Mus Natural Immunity Neutrophil Infiltration Oral Oral cavity Organism Pathway interactions Periodontal Diseases Periodontitis Periodontium Phosphorylation Phosphotransferases Porphyromonas gingivalis Predisposition Production Protein-Serine-Threonine Kinases Publications Role Serum Severities Signal Pathway Signal Transduction Signaling Molecule TNF gene Testing Time Tissues Work alveolar bone bone loss cytokine design dysbiosis in vivo inhibitor/antagonist insight macrophage microbial microbial community monocyte novel novel therapeutic intervention oral bacteria oral infection oral microbial community oral pathogen oral tissue p65 pathogen prevent recruit response subcutaneous targeted agent therapeutic target

项目摘要

Abstract Host inflammatory immune responses to oral microbiota are tightly regulated by multiple pro-inflammatory and anti-inflammatory mechanisms. The balance of there two activities ensures a state of immune homeostasis which is critical for protecting against microbial invasion and avoiding subsequent collateral tissue damages. To limit the ferocity of inflammation, a number of established pathways exist that dampen the innate immune response. Our recent publication has demonstrated a novel role for serum- and glucocorticoid- inducible kinase 1 (SGK1), a serine/threonine kinase associated with the PI3K pathway, in restraining the production of E. coil LPS-mediated pro-inflammatory cytokine production in human monocytes. Preliminary data for this application show for the first time that SGK1 is phospho-activated in human monocytes in response to challenge with multiple oral bacteria. In addition, using P. gingivalis, a well-established model oral organism for the investigation of host-pathogen interactions in the periodontium, we show that inhibition of SGK1 robustly enhances the production of pro-inflammatory cytokines (TNF, IL-12, IL-6, IL-1β, IL-8) and reduces IL-10 levels, a result also confirmed by using Cre-loxP-mediated SGK1 knockout mice. Moreover, the anti-inflammatory role for SGK1 was validated by our preliminary in vivo evidence showing that systemic administration of the SGK1 inhibitor, EMD638683, elevated infiltration of neutrophils and macrophages into the gingival tissues and aggravated the severity of alveolar bone resorption in mice orally infected with P. gingivalis. Thus, we have identified a novel role for SGK1 as a negative regulator of inflammation, and propose that stimulation of this endogenous anti-inflammatory pathway in the host will help limit or prevent P. gingivalis-induced tissue destruction. The specific hypothesis to be tested in this application is that in the context of P. gingivalis challenge, SGK1 constrains the production of pro-inflammatory cytokines; down-regulates recruitment of inflammatory cells to the periodontium; and in turn protects against alveolar bone loss through downstream modification of inflammatory signaling molecules including Nedd4-2, MKP-1, and TAK1, which ultimately converge on NF-κB. We will challenge this hypothesis with three specific Aims: (i) To characterize SGK1 as an innate immune suppressor of inflammatory responses in vitro; (ii) To elucidate the signaling mechanisms by which SGK1 controls host inflammatory responses; and (iii) To establish the in vivo relevance of SGK1 in the control of host inflammation using mouse subcutaneous chamber and alveolar bone loss models. Successful completion of these studies will characterize, for the first time, the anti-inflammatory function of SGK1 in host inflammatory responses to P. gingivalis, and elucidate the novel anti-inflammatory signaling network mediated by the SGK1-MKP1 module in the control of the inflammation progression. In the long term, this work could pave the way for the development of novel anti-inflammatory agents targeting SGK1 or MKP-1 to ameliorate or prevent not only P. gingivalis-induced tissue destruction, but other inflammatory disorders. Such an approach has relevance both for periodontal disease and for chronic inflammatory conditions in general.

抽象的宿主对口腔微生物群的炎症免疫反应受到多种促炎和这两种活性的平衡确保了免疫稳态的状态。这对于防止微生物入侵和避免随后的附带组织损伤至关重要。为了限制炎症的严重程度，存在许多抑制先天免疫的既定途径我们最近的出版物证明了血清和糖皮质激素诱导的新作用。激酶 1 (SGK1) 是一种与 PI3K 通路相关的丝氨酸/苏氨酸激酶，可抑制 E.coil LPS 介导的人类单核细胞中促炎细胞因子的产生。应用首次表明 SGK1 在人类单核细胞中被磷酸激活，以响应此外，还使用牙龈卟啉单胞菌（一种成熟的模型口腔生物体）进行挑战。为了研究牙周组织中宿主与病原体的相互作用，我们发现 SGK1 的抑制可有效抑制增强促炎细胞因子（TNF、IL-12、IL-6、IL-1β、IL-8）的产生并降低 IL-10 水平，使用 Cre-loxP 介导的 SGK1 敲除小鼠也证实了这一结果，并且具有抗炎作用。 SGK1 的作用得到了我们初步体内证据的验证，表明全身给药 SGK1 SGK1 抑制剂 EMD638683 增加中性粒细胞和巨噬细胞向牙龈组织的浸润，加重了口服感染牙龈卟啉单胞菌的小鼠牙槽骨吸收的严重程度。确定了 SGK1 作为炎症负调节因子的新作用，并提出刺激这种作用宿主内源性抗炎途径将有助于限制或预防牙龈卟啉单胞菌诱导的组织本申请中要测试的具体假设是在牙龈卟啉单胞菌的背景下。挑战时，SGK1 限制促炎细胞因子的产生；炎症细胞进入牙周组织，进而防止牙槽骨流失炎症信号分子的下游修饰，包括 Nedd4-2、MKP-1 和 TAK1，最终收敛于 NF-κB 我们将通过三个具体目标挑战这一假设：(i) 将 SGK1 描述为体外炎症反应的先天免疫抑制剂； SGK1 控制宿主炎症反应的信号机制；以及 (iii) 建立体内 SGK1 在使用小鼠皮下腔和牙槽骨控制宿主炎症中的相关性这些研究的成功完成将首次表征抗炎作用。 SGK1 在宿主对牙龈卟啉单胞菌炎症反应中的功能，并阐明新型抗炎药物 SGK1-MKP1 模块介导的信号网络控制炎症进展。从长远来看，这项工作可能为开发针对 SGK1 的新型抗炎药物铺平道路或 MKP-1 不仅可以改善或预防牙龈卟啉单胞菌引起的组织破坏，还可以改善或预防其他炎症这种方法对于牙周病和慢性炎症都有相关性。条件一般。