Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.
Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses.
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DOI：
10.4049/jimmunol.1000866
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发表时间：
2010-07-15
期刊：
影响因子：
--
通讯作者：
Schlesinger LS
中科院分区：
文献类型：
--
作者：
Rajaram MV;Brooks MN;Morris JD;Torrelles JB;Azad AK;Schlesinger LS
结核分枝杆菌通过部分通过其复杂的细胞壁结构抑制免疫反应来提高其在巨噬细胞中的存活率。过氧化物酶体增殖物激活受体γ(PPARγ)是核受体超家族成员之一，是一种调节炎症的转录因子，在交替激活的肺泡巨噬细胞和巨噬细胞源性泡沫细胞中高表达，这两种细胞类型都与结核病的发病机制有关。在本研究中，我们发现结核分枝杆菌毒力株及其细胞壁的甘露糖脂阿拉伯甘露聚糖通过巨噬细胞甘露糖受体依赖的途径诱导PPARγ的表达。当被激活时，PPARγ促进IL-8和环氧合酶2的表达，这一过程受PPARγ激动剂或拮抗剂的调节。上游，MAPK-p38介导胞浆磷脂酶A2的激活，这是产生PPARγ配体所必需的。甘露糖修饰的阿拉伯甘露糖和甘露糖受体介导的IL-8反应不依赖于TLR2和NF-κB的激活。相反，减毒的牛分枝杆菌卡介苗诱导的PPARγ较少，并优先使用核因子-κB介导的途径来诱导IL-8的产生。最后，在人的巨噬细胞中敲除PPARγ可以增加肿瘤坏死因子的产生，并控制结核分枝杆菌在细胞内的生长。这些数据确定了一条新的分子途径，该途径将结核分枝杆菌的重要模式识别受体甘露糖受体与调节巨噬细胞炎症反应的PPARγ激活联系起来，从而在结核病发病机制中发挥作用。
Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARγ expression through a macrophage mannose receptor-dependent pathway. When activated, PPARγ promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARγ agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A2 activation, which is required for PPARγ ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-κB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARγ and preferentially uses the NF-κB–mediated pathway to induce IL-8 production. Finally, PPARγ knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARγ activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.
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DOI：
10.1073/pnas.0904846106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Day, Judy;Friedman, Avner;Schlesinger, Larry S.
通讯作者：
Schlesinger, Larry S.
影响因子：
64.8
作者：
Jiang, CY;Ting, AT;Seed, B
通讯作者：
Seed, B
影响因子：
4.4
作者：
Henning, Lisa N.;Azad, Abul K.;Schlesinger, Larry S.
通讯作者：
Schlesinger, Larry S.
影响因子：
56.9
作者：
LARSEN, CG;ANDERSON, AO;MATSUSHIMA, K
通讯作者：
MATSUSHIMA, K
人类巨噬细胞甘露糖受体指导结核分枝杆菌脂肪氨基氨基甘氨酸介导的吞噬体生物发生。
DOI：
10.1084/jem.20051239
发表时间：
2005-10-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kang PB;Azad AK;Torrelles JB;Kaufman TM;Beharka A;Tibesar E;DesJardin LE;Schlesinger LS
通讯作者：
Schlesinger LS