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首页> 外文期刊>Infection and immunity >Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells
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Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

机译：在结核分枝杆菌感染的巨噬细胞中类似Toll的受体2依赖性细胞外信号调节激酶信号驱动抗炎反应并抑制响应T细胞的极化。

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Mycobacterium tuberculosis survives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrict M. tuberculosis to latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by which M. tuberculosis modulates host responses to promote its survival remain unclear. In these studies, we demonstrate that M. tuberculosis induction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion of Tpl2 blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate that M. tuberculosis regulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway in Tpl2?/? macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4+ T cells responding to M. tuberculosis infection. These data indicate that M. tuberculosis and its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.
机译：结核分枝杆菌在巨噬细胞内存活，并利用免疫逃逸机制持续存在于宿主中。诱导了1型保护性T辅助反应（Th1），大多数人的免疫反应足以将结核分枝杆菌限制为潜伏感染，但大多数感染并未完全解决。随着T细胞和巨噬细胞的反应，在与Th1相关的保护性和其他促炎细胞因子（例如白介素12（IL-12），干扰素γ（IFN-γ）和肿瘤坏死因子α）与抗炎性之间建立起平衡细胞因子，例如IL-10。结核分枝杆菌调节宿主反应以促进其存活的机制仍不清楚。在这些研究中，我们证明结核分枝杆菌对IL-10的诱导，IL-12的抑制以及感染巨噬细胞中II类主要组织相容性复合物（MHC-II）分子的抑制均由Toll样受体2（TLR2）驱动依赖的细胞外信号调节激酶（ERK）的激活。通过U0126的药理抑制或 Tpl2 的基因缺失消除TLR2下游ERK信号传导，从而阻断IL-10分泌并增强IL-12 p70分泌。我们证明在巨噬细胞中这些途径的结核分枝杆菌调节影响T细胞对感染巨噬细胞的反应。因此，对 Tpl2 ？/？巨噬细胞中ERK途径的遗传封锁可通过抗原特异性CD4 + T增强Th1极化和IFN-γ的产生。对结核分枝杆菌感染有反应的细胞。这些数据表明结核分枝杆菌及其有效的TLR2配体激活巨噬细胞中的ERK信号传导，从而促进抗炎性巨噬细胞应答并钝化针对病原体的Th1应答。

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