TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
基本信息
- 批准号:8616331
- 负责人:
- 金额:$ 39.75万
- 依托单位:
- 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:
- 关键词:AerosolsAffectAnimalsAnti-Inflammatory AgentsAnti-inflammatoryB-LymphocytesBacteriaBacteriophagesBreathingCellsChronicCommunicationContainmentDendritic CellsEquilibriumExhibitsExtracellular MatrixFibroblastsGene ExpressionGene Expression ProfileGenesGenus MycobacteriumGranulomaGranulomatousHost DefenseHost resistanceImmuneImmune responseImmunityImmunocompetentIndividualInfectionInfiltrationInflammationInflammatoryInflammatory ResponseInterleukin-1Interleukin-12Knockout MiceKnowledgeLaboratoriesLungMaintenanceMatrix MetalloproteinasesMediatingMemoryMitogen-Activated Protein KinasesMusMycobacterium tuberculosisPathologicPathologyPathway interactionsPhagocytosisPhosphotransferasesPlayProcessProductionRecruitment ActivityRegulatory T-LymphocyteReportingRoleSeriesSignal PathwaySignal TransductionStructureT-Cell ActivationT-LymphocyteTestingTimeToll-Like Receptor 2Tuberculosisantimicrobialbasecytokineexpectationimmunopathologyin vivoinhibitor/antagonistinsightmacrophagenovelpathogenpreventresponse
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,我们将探讨以下假设:Toll样受体2(TLR2)是控制结节肉芽肿的保护性和病理特征的主调节器。该假设建立在我们实验室中的新发现。以前,我们已经报道了TLR9和TLR2在结核分枝杆菌(MTB)感染的树突状细胞(DCS)中分别诱导促炎和抗炎细胞因子,而TLR2在感染巨噬细胞中诱导促促促促血统和抗炎细胞因子。基于这些观察结果的合理预测是,在MTB感染期间,由TLR2触发的先天抗炎反应可能控制Th1效应子和记忆T细胞激活的大小。与预期相反,我们发现TLR2的不存在不会影响用MTB感染气溶胶感染后产生的Th1效应子响应的大小,也不会影响MTB挑战的回忆TH1记忆免疫。然而,TLR2缺乏宿主电阻的后果在颗粒瘤的水平上表现出来。 TLR2KO小鼠感染的肺表现出增强的炎症,与降低Foxp3 [+] T调节细胞(Tregs)浸润降低有关,而受感染的WT动物的肺则解决了它们的炎症,并具有小的,紧凑的肉芽肿。 Treg已被证明阻止了针对持续病原体的抗菌反应。令人惊讶的是,尽管没有Tregs,但与感染的WT小鼠相比,长期感染的TLR2KO小鼠的肺表现出增强的细菌负担和肉芽肿完整性的丧失,表明迄今表明TLR2对TLR2的作用不足,用于控制抗蛋白酶抗菌反应的果皮瘤。初步基因表达研究表明TLR2诱导的基质金属蛋白酶在调节肉芽肿成熟中的作用。
该提案将测试以下特定假设:i)TLR2诱导的MMP调节肉芽肿成熟; ii)TLR2对于控制颗粒瘤内MTB复制和遏制的巨噬细胞至关重要; iii)TLR2诱导TREG,主要作为肺部免疫病理学抑制剂,但不是巨噬细胞抗菌反应的抑制剂; iv)TLR2-tigggggggggggggggggggggggggaggage和v)信号通路相互调节,MTB可以使途径自身受益。提出的研究中的集体发现将提供有关结节肉芽肿中TLR2触发的信号通路的见解,以及可以通过治疗进行操纵的独特方法。
项目成果
期刊论文数量(0)
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