Unité d'Immunobiologie de l'Infection, INSERM U1221, Institut Pasteur, Paris, France.
Université Paris Diderot, Paris, France.
Front Immunol. 2018 Jan 19;9:2. doi: 10.3389/fimmu.2018.00002. eCollection 2018.
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 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.
酚甘油酯（PGLs）是一组致病性分枝杆菌细胞壁的组成部分，具有免疫调节特性。在这里，我们表明，PGLs 通过限制分枝杆菌感染的巨噬细胞中一氧化氮合酶（iNOS）的产生来发挥杀菌活性。PGL 介导的 iNOS 下调依赖于补体受体 3，并且细菌和纯化的 PGLs 可产生相当的诱导作用。使用 PGL-1 作为模型，我们发现 PGLs 抑制了 Toll 样受体（TLR）4 信号通路，巨噬细胞暴露于 PGLs 导致 TIR 结构域包含衔接诱导干扰素-β（TRIF）蛋白水平显著降低。PGL 驱动的 TRIF 减少是在转录后进行的，并且不依赖于Src 家族酪氨酸激酶、溶酶体和蛋白酶体降解。它导致 TLR4 刺激的巨噬细胞中 TRIF 依赖性 IFN-β 和 CXCL10 的产生缺陷，除了 iNOS。我们的研究结果揭示了 PGLs 劫持宿主巨噬细胞杀菌和炎症反应的机制。此外，它们确定 TRIF 是 CR3 和 TLR4 之间相互作用的关键节点。
