Mycobacterium tuberculosis Modulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival
Mycobacterium tuberculosis Modulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival
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DOI：
10.4049/jimmunol.1103038
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Gupta, Pawan
中科院分区：
文献类型：
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作者：
Mahajan, Sahil;Dkhar, H. Kitdorlang;Gupta, Pawan
结核分枝杆菌-巨噬细胞相互作用是这些细菌的发病机制和清除的关键。虽然M.尽管已经研究了结核病相关的脂质和TLR、非TLR和调理素受体，但这些脂质和感染的巨噬细胞脂质库与巨噬细胞中表达的脂质敏感核受体的相互作用尚未得到解决。在这项研究中，我们报告说，M。结核-巨噬细胞脂质可与宿主过氧化物酶体增殖物激活受体γ和睾丸受体4相互作用，以通过调节巨噬细胞功能来确保病原体的存活。这两种脂质敏感核受体通过调节氧化低密度脂蛋白受体CD 36在巨噬细胞内产生泡沫龛，通过诱导IL-10阻断吞噬溶酶体成熟，以及通过巨噬细胞的交替极化钝化先天反应，这导致M存活。结核这些结果也表明可能的过氧化物酶体增殖物激活受体γ和睾丸受体4的异源配体，并提示适应性或共同进化的主机和病原体。这些受体的相对mRNA表达水平的PBMC来源于临床样品令人信服地牵连他们在结核病的易感性。这些观察揭示了M.结核病适合于药物调节。免疫学杂志，2012，188：5593-5603。
Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor gamma and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor gamma and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation. The Journal of Immunology, 2012, 188: 5593-5603.