Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages.
Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages.
复制标题
分枝杆菌酚类糖脂在巨噬细胞中选择性禁用TRIF依赖性TLR4信号。
DOI：
10.3389/fimmu.2018.00002
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发表时间：
2018
影响因子：
7.3
通讯作者：
Demangel C
中科院分区：
文献类型：
--
作者：
Oldenburg R;Mayau V;Prandi J;Arbues A;Astarie-Dequeker C;Guilhot C;Werts C;Winter N;Demangel C
酚醛糖脂(PGL)是一类致病分支杆菌的细胞壁成分，具有免疫调节作用。在这里，我们表明，此外，PGLS通过限制分枝杆菌感染的巨噬细胞中一氧化氮合酶(INOS)的产生而发挥抗菌活性。PGL介导的iNOS下调是补体受体3依赖的，细菌和纯化的PGL诱导的iNOS下调作用相似。以麻风分枝杆菌PGL-1为模型，我们发现PGLS抑制了Toll样受体(TLR4)信号通路，巨噬细胞暴露于PGLS后，含有TIR结构域的适配器诱导干扰素-β(TRIF)蛋白水平显著降低。PGL导致的TRIF的减少是转录后操作的，并且不依赖于Src家族酪氨酸激酶、溶酶体和蛋白酶体的降解。这导致TLR4刺激的巨噬细胞产生依赖于TRIF的干扰素-β和CXCL10，以及诱导型一氧化氮合酶。我们的结果揭示了PGLS劫持宿主巨噬细胞杀菌和炎症反应的机制。此外，他们认为TRIF是CR3和TLR4之间串扰的关键节点。
Phenolic glycolipids (PGLs) are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS) in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR)4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-β (TRIF) protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-β and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.