TLR2 and the Tubercle Granuloma

TLR2 和结节肉芽肿

• 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
• 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

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.

在本申请中，我们将探讨Toll样受体2（TLR 2）是控制结核肉芽肿的保护和病理特征的主调节器的假设。这个假设建立在我们实验室的新发现之上。以前我们曾报道过TLR 9和TLR 2在M. TLR 2在结核病（Mtb）感染的树突状细胞（DC）中诱导促炎细胞因子和抗炎细胞因子，而TLR 2在感染的巨噬细胞中诱导促炎细胞因子和抗炎细胞因子。基于这些观察，合理的预测是，在结核分枝杆菌感染期间，由TLR 2触发的先天性抗炎反应可能控制Th 1效应和记忆T细胞活化的幅度。与预期相反，我们发现TLR 2的缺乏并不影响Mtb气溶胶感染后产生的Th 1效应器应答的幅度，也不影响响应Mtb挑战的回忆性Th 1记忆免疫的诱导。然而，TLR 2缺乏宿主抗性的后果表现在肉芽肿水平。TLR 2KO小鼠感染的肺表现出与FoxP 3 [+] T调节细胞（TCFs）向肺中的浸润减少相关的炎症增强，而感染的WT动物的肺已解决其炎症并具有小而致密的肉芽肿。已显示THEORY阻碍宿主对持久性病原体的抗菌反应。令人惊讶的是，尽管不存在TLR 2，但与感染的WT小鼠相比，来自慢性感染的TLR 2KO小鼠的肺表现出增强的细菌负荷和肉芽肿完整性的丧失，表明TLR 2在肉芽肿中控制体内抗微生物应答中的作用迄今未被充分认识。初步的基因表达研究指出TLR 2诱导的基质金属蛋白酶在调节肉芽肿成熟中的作用。 在该提案中将测试以下具体假设：i）TLR 2诱导的MMP调节肉芽肿成熟; ii）TLR 2对于肉芽肿内Mtb复制和遏制的巨噬细胞控制是必需的; iii）TLR 2诱导主要作为肺免疫病理学的抑制剂而不是巨噬细胞抗微生物应答的抑制剂起作用的TcR; iv）TLR 2-触发两种不同的信号传导途径，用于在Mtb-感染的巨噬细胞内诱导促炎性细胞因子和抗炎性细胞因子的产生，以及v）信号传导途径相互交叉调节，并且Mtb可以操纵该途径以使其自身受益。从拟议的研究的集体发现将提供深入了解TLR 2触发的信号通路在结核肉芽肿和独特的方式，他们可以在治疗上操纵。