Mycobacterium bovis bacillus calmette-guerin induces TLR2-mediated formation of lipid bodies:: Intracellular domains for eicosanoid synthesis in vivo
Mycobacterium bovis bacillus calmette-guerin induces TLR2-mediated formation of lipid bodies:: Intracellular domains for eicosanoid synthesis in vivo
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DOI：
10.4049/jimmunol.176.5.3087
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发表时间：
2006-03-01
影响因子：
4.4
通讯作者：
Bozza, Patricia T.
中科院分区：
文献类型：
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作者：
D'Avila, Heloisa;Melo, Rossana C. N.;Bozza, Patricia T.
巨噬细胞分化为泡沫状（充满脂质）巨噬细胞是结核性肉芽肿中常见的病理学观察结果，无论是在实验环境中还是在临床条件下;然而，在分枝杆菌感染过程中调节细胞内脂质积聚的机制及其对结核病病理生理学的意义尚不清楚。在这项研究中，我们研究了结核病小鼠模型中脂质巨噬细胞的形成和功能机制。牛分枝杆菌卡介苗（BCG），但不是耻垢分枝杆菌，诱导脂质体诱导的非膜结合胞质脂质结构域的大小和数量的剂量和时间依赖性增加。脂质体的形成在TLR 2-，但不是在TLR 4-缺陷的小鼠，表明TLR 2在BCG识别和信号传导形成脂质体的作用。感染期间脂质体的增加与PGE（2）的产生增加和脂质体内环氧合酶-2的定位有关。此外，我们通过新形成的类二十烷酸的细胞内免疫荧光定位证明，脂质体是活化的巨噬细胞中PGE（2）合成的主要位点。我们的研究结果表明，BCG诱导的脂质体形成是TLR 2介导的，这些结构在炎症介质产生中起信号平台的作用，因为脂质体内底物和关键酶的区室化影响了活化白细胞在BCG实验感染期间产生增加量的类花生酸的能力。
Differentiation of macrophages into foamy (lipid-laden) macrophages is a common pathological observation in tuberculous granulomas both in experimental settings as well as in clinical conditions; however, the mechanisms that regulate intracellular lipid accumulation in the course of mycobacterial infection and their significance to pathophysiology of tuberculosis are not well understood. In this study, we investigated the mechanisms of formation and function of lipid-laden macrophages in a murine model of tuberculosis. Mycobacterium bovis bacillus Calmette-Guerin (BCG), but not Mycobacterium smegmatis, induced a dose- and time-dependent increase in lipid body-inducible nonmembrane-bound cytoplasmic lipid domain size and numbers. Lipid body formation was drastically inhibited in TLR2-, but not in TLR4-deficient mice, indicating a role for TLR2 in BCG recognition and signaling to form lipid bodies. Increase in lipid bodies during infection correlated with increased generation of PGE(2) and localization of cyclooxygenase-2 within lipid bodies. Moreover, we demonstrated by intracellular immunofluorescent localization of newly formed eicosanoid that lipid bodies were the predominant sites of PGE(2) synthesis in activated macrophages. Our findings demonstrated that BCG-induced lipid body formation is TLR2 mediated and these structures function as signaling platforms in inflammatory mediator production, because compartmentalization of substrate and key enzymes within lipid bodies has impact on the capacity of activated leukocytes to generate increased amounts of eicosanoids during experimental infection by BCG.