xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation.

Abstract

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.

• Authors: Yi Cai, Qianting Yang, Mingfeng Liao, Hao Wang, Chi Zhang, Subhalaxmi Nambi, Wenfei Wang, Mingxia Zhang, Junying Wu, Guofang Deng, Qunyi Deng, Haiying Liu, Boping Zhou, Qi Jin, Carl G Feng, Christopher M Sassetti, Fudi Wang, Xinchun Chen
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 21 Pg. 31001-13 (May 24 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27129162 (Publication Type: Journal Article)

Chemical References

• Amino Acid Transport System y+
• Anti-Infective Agents
• SLC7A11 protein, human
• Slc7a11 protein, mouse
• Sulfasalazine

Topics

• Amino Acid Transport System y+ (antagonists & inhibitors, blood, immunology)
• Animals
• Anti-Infective Agents (pharmacology)
• Case-Control Studies
• Cell Line, Tumor
• Disease Susceptibility
• Humans
• Inflammation (immunology, metabolism, microbiology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (immunology, metabolism)
• Oxidation-Reduction
• Sulfasalazine (pharmacology)
• Tuberculosis (blood, drug therapy, immunology, pathology)