xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.
xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.
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xCT 通过调节抗菌功能和炎症来增加结核病易感性
DOI：
10.18632/oncotarget.9052
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Cai Y;Yang Q;Liao M;Wang H;Zhang C;Nambi S;Wang W;Zhang M;Wu J;Deng G;Deng Q;Liu H;Zhou B;Jin Q;Feng CG;Sassetti CM;Wang F;Chen X
巨噬细胞的氧化还原状态决定其生理功能，在结核病的发病机制中起着重要作用。系统xc-是一种胱氨酸-谷氨酸转运蛋白，由xCT和CD 98组成，通过调节抗氧化剂谷胱甘肽的产生来影响许多ROS依赖性途径。xCT通过增加吞噬细胞生理学的谷胱甘肽合成方面来改变这种关键宿主氧化还原平衡的能力表明其可能影响结核病发病机制。本研究发现活动性结核患者外周血单核细胞中xCT表达增加。结核分枝杆菌（Mycobacterium tuberculosis，Mtb）通过TLR 2/Akt-和p38-依赖的信号通路诱导巨噬细胞表达xCT。重要的是，xCT缺陷赋予针对结核病的保护，因为与野生型小鼠相比，xCT敲除小鼠显示出增加的Mtb负荷和减少的肺病理学。xCT破坏通过增加真菌硫醇氧化来增强巨噬细胞的杀真菌活性。重要的是，用柳氮磺胺吡啶（一种已被FDA批准用于治疗炎症性肠病的特异性xCT抑制剂）化学抑制xCT，在体内和体外产生类似的保护作用，表明xCT可能是宿主导向的TB治疗策略的一种新的有用靶点。
The physiological functions of macrophage, which plays a central role in the pathogenesis of tuberculosis, depend on its redox state. System xc-, a cystine-glutamate transporter, which consists of xCT and CD98, influences many ROS-dependent pathways by regulating the production of the antioxidant glutathione. xCT's ability to alter this critical host redox balance by increasing the glutathione synthesis aspect of phagocyte physiology suggested that it might influence tuberculosis pathogenesis. In this study, we found that the xCT expression was increased in peripheral blood monocyte of active tuberculosis. xCT expression in macrophage was induced by Mycobacterium tuberculosis (Mtb) through TLR2/Akt- and p38-dependent signaling pathway. Importantly, xCT deficiency conferred protection against tuberculosis, as xCT knock out mice displayed increased Mtb load and reduced pulmonary pathology in lung compared to wild type mice. xCT disruption enhanced the mycobateriacidal activity of macrophage through increasing the mycothiol oxidation. Importantly, chemical inhibition of xCT with sulfasalazine, a specific xCT inhibitor that is already approved by the FDA for treatment of inflammatory bowel disease, produces similar protective effects in vivo and in vitro, indicating xCT might be a novel and useful target for host-directed TB treatment strategy.
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