Inflammatory signaling in human tuberculosis granulomas is spatially organized.
Inflammatory signaling in human tuberculosis granulomas is spatially organized.
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DOI：
10.1038/nm.4073
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发表时间：
2016-05
期刊：
影响因子：
82.9
通讯作者：
Rubin EJ
中科院分区：
文献类型：
--
作者：
Marakalala MJ;Raju RM;Sharma K;Zhang YJ;Eugenin EA;Prideaux B;Daudelin IB;Chen PY;Booty MG;Kim JH;Eum SY;Via LE;Behar SM;Barry CE 3rd;Mann M;Dartois V;Rubin EJ
肉芽肿是结核病（TB）的病理标志。然而，它们的功能和形成机制仍然知之甚少。为了了解肉芽肿在结核病中的作用，我们以无偏的方式分析了结核病患者肉芽肿的蛋白质组。使用激光捕获显微切割，质谱和共聚焦显微镜，我们产生了详细的人类肉芽肿的分子图谱。我们发现肉芽肿中心具有以抗微生物肽、ROS和促炎性类花生酸为特征的促炎环境。相反，干酪周围的组织具有相对的抗炎特征。这些发现在一组6名受试者和家兔中是一致的。虽然系统性促炎和抗炎信号之间的平衡对结核病的结果至关重要，但我们发现这些信号在每个肉芽肿中是物理分离的。本文分析的人和兔病变的蛋白质和脂质快照表明，对TB的病理反应是由肉芽肿发展过程中这些炎症通路的精确解剖定位形成的。
Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased fashion. Using laser capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas possess a pro-inflammatory environment characterized by anti-microbial peptides, ROS and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum possesses a comparatively anti-inflammatory signature. These findings are consistent across a set of six subjects and in rabbits. While the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. The protein and lipid snapshots of human and rabbit lesions analysed here suggest that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.