Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York, United States of America.
PLoS One. 2010 Sep 15;5(9):e12772. doi: 10.1371/journal.pone.0012772.
The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection.
Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation.
In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection.
内质网（ER）应激途径，即未折叠蛋白反应（UPR），是一种适应性生存途径，可保护细胞免受错误折叠蛋白的积累，但在某些情况下，它可能导致细胞凋亡。内质网应激与小鼠和人类晚期动脉粥样硬化中的巨噬细胞凋亡有关。由于动脉粥样硬化与结核病（TB）在病变部位巨噬细胞积累、泡沫细胞形成和凋亡方面具有某些共同特征，我们研究了内质网应激途径是否在 TB 感染期间被激活。
在这里，我们发现 ER 应激标志物，如 C/EBP 同源蛋白（CHOP；也称为 GADD153）、磷酸化肌醇需求酶 1α（Ire1α）和真核起始因子 2α（eIF2α）以及激活转录因子 3（ATF3），在感染毒力结核分枝杆菌（Mtb）的小鼠肺部的肉芽肿中富含巨噬细胞的区域表达。这些区域也通过 TUNEL 检测呈大量凋亡细胞阳性。通过激光捕获显微切割分离的人干酪样 TB 肉芽肿的微阵列分析显示，UPR 中 73%的基因在 mRNA 转录水平上调。通过免疫组织化学检测，人 TB 肉芽肿中两种 ER 应激标志物 ATF3 和 CHOP 的表达也增加。CHOP 已被证明与 ER 应激诱导的巨噬细胞凋亡有关。我们发现，与从患有肺结核的患者中分离的非肉芽肿组织相比，在肉芽肿中凋亡更为丰富，并且凋亡与中央干酪样区域周围区域的 CHOP 表达相关。
总之，在小鼠和人类中，在含有凋亡细胞的 TB 肉芽肿的巨噬细胞中诱导了内质网应激。尽管巨噬细胞凋亡通常被认为有助于最初保护宿主免受 Mtb 感染，但在晚期肉芽肿中感染的巨噬细胞死亡可能有利于细菌的传播。因此，需要进一步研究内质网应激是否是导致细胞凋亡的原因，并在宿主对感染的反应中发挥作用。
