TLR2 and the Tubercle Granuloma

TLR2 和结节肉芽肿

基本信息

批准号：
8231291
负责人：
Padmini Salgame
金额：
$ 39万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231291
关键词：
Aerosols Affect Animals Anti-Inflammatory Agents Anti-inflammatory B-Lymphocytes Bacteria Bacteriophages Breathing Cells Chronic Communication Containment Dendritic Cells Equilibrium Exhibits Extracellular Matrix Fibroblasts Gene Expression Gene Expression Profile Genes Genus Mycobacterium Granuloma Granulomatous Host Defense Host resistance Immune Immune response Immunity Immunocompetent Individual Infection Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-12 Knockout Mice Knowledge Laboratories Lung Maintenance Matrix Metalloproteinases Mediating Memory Mitogen-Activated Protein Kinases Mus Mycobacterium tuberculosis Pathologic Pathology Pathway interactions Phagocytosis Phosphotransferases Play Process Production Recruitment Activity Regulatory T-Lymphocyte Reporting Role Series Signal Pathway Signal Transduction Structure T-Cell Activation T-Lymphocyte Testing Time Toll-Like Receptor 2 Tuberculosis antimicrobial base cytokine expectation immunopathology in vivo inhibitor/antagonist insight macrophage novel pathogen prevent response

项目摘要

In this application we will explore the hypothesis that Toll-like receptor 2 (TLR2) is the master regulator controlling both protective and pathologic features of the tubercle granuloma. The hypothesis builds on novel findings made in our laboratory. Previously we had reported that TLR9 and TLR2 induce pro- and anti-inflammatory cytokines, respectively, in M. tuberculosis (Mtb)-infected dendritic cells (DCs), while TLR2 induces both pro- and anti-inflammatory cytokines in infected macrophages. A reasonable prediction, based on these observations, is that during Mtb infection the innate anti-inflammatory response triggered by TLR2 may control the magnitude of Th1 effector and memory T cell activation. Contrary to expectation, we found that the absence of TLR2 did not affect the magnitude of the Th1 effector response generated following aerosol infection with Mtb or the induction of recall Th1 memory immunity in response to Mtb challenge. However, the consequence of TLR2 absence to host resistance was manifested at the level of the granuloma. The infected lungs of TLR2KO mice exhibited enhanced inflammation associated with reduced infiltration of FoxP3[+] T regulatory cells (Tregs) into the lung, while lungs from infected WT animals had resolved their inflammation and had small, compact granulomas. Tregs have been shown to thwart host antimicrobial responses against persistent pathogens. Surprisingly, despite the absence of Tregs, lungs from chronically-infected TLR2KO mice exhibited enhanced bacterial burden and loss of granuloma integrity in comparison with infected WT mice indicating a hitherto under-appreciated role for TLR2 in controlling antimicrobial responses in vivo in the granuloma. Preliminary gene expression studies point to the role of TLR2-induced matrix metaloproteinases in regulating granuloma maturation. The following specific hypotheses will be tested in the proposal: i) TLR2-induced MMPs regulate granuloma maturation; ii)TLR2 is essential for macrophage control of Mtb replication and containment within the granuloma; iii) TLR2 induces Tregs which operate primarily as inhibitors of lung immune pathology but not as inhibitors of macrophage antimicrobial responses; iv) TLR2-triggers two distinct signaling pathways for the induction of pro- and anti-inflammatory cytokine production within Mtb- infected macrophages, and v) the signaling pathways cross-regulate each other and Mtb can maneuver the pathways to its own benefit. The collective findings from the proposed studies will provide insights into TLR2-triggered signaling pathways in the tubercle granuloma and unique ways in which they can be manipulated therapeutically.

在此应用中，我们将探讨 Toll 样受体 2 (TLR2) 是控制结节肉芽肿的保护性和病理性特征的主要调节因子的假设。该假设建立在我们实验室的新发现之上。之前我们报道过，TLR9和TLR2在结核分枝杆菌（Mtb）感染的树突状细胞（DC）中分别诱导促炎和抗炎细胞因子，而TLR2在感染的巨噬细胞中诱导促炎和抗炎细胞因子。基于这些观察结果，一个合理的预测是，在 Mtb 感染期间，TLR2 触发的先天抗炎反应可能控制 Th1 效应器和记忆 T 细胞激活的程度。与预期相反，我们发现TLR2的缺失并不影响Mtb气溶胶感染后产生的Th1效应反应的强度，也不会影响针对Mtb攻击的Th1记忆免疫回忆的诱导。然而，TLR2 缺失对宿主抵抗力的影响体现在肉芽肿水平上。 TLR2KO 小鼠受感染的肺部表现出与 FoxP3+T 调节细胞 (Treg) 向肺部浸润减少相关的炎症增强，而受感染的 WT 动物的肺部炎症已消退，并出现小而致密的肉芽肿。 Tregs 已被证明可以阻止宿主针对持久性病原体的抗菌反应。令人惊讶的是，尽管不存在 Tregs，但与感染的 WT 小鼠相比，长期感染的 TLR2KO 小鼠的肺部表现出细菌负荷增加和肉芽肿完整性丧失，这表明 TLR2 在控制体内肉芽肿抗菌反应方面的作用迄今未被充分认识。初步基因表达研究指出 TLR2 诱导的基质金属蛋白酶在调节肉芽肿成熟中的作用。该提案将测试以下具体假设： i) TLR2 诱导的 MMP 调节肉芽肿成熟； ii)TLR2对于巨噬细胞控制结核分枝杆菌复制和抑制肉芽肿内至关重要； iii) TLR2诱导Tregs主要作为肺免疫病理学的抑制剂，但不作为巨噬细胞抗菌反应的抑制剂； iv) TLR2 触发两条不同的信号传导途径，以诱导 Mtb 感染的巨噬细胞内促炎和抗炎细胞因子的产生，v) 信号传导途径相互交叉调节，Mtb 可以操纵这些途径以达到自身的利益。拟议研究的集体发现将为结节肉芽肿中 TLR2 触发的信号通路及其独特的治疗方法提供见解。