Research Papers:

xCT increases tuberculosis susceptibility by regulating antimicrobial function and inflammation

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 _ and Xinchun Chen

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Oncotarget. 2016; 7:31001-31013. https://doi.org/10.18632/oncotarget.9052

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Yi Cai1,2,*, Qianting Yang1,2,*, Mingfeng Liao1,2,*, Hao Wang3,*, Chi Zhang1,7, Subhalaxmi Nambi5, Wenfei Wang1,2, Mingxia Zhang1,2, Junying Wu7, Guofang Deng1, Qunyi Deng2, Haiying Liu8,9, Boping Zhou1, Qi Jin8,9, Carl G Feng4, Christopher M Sassetti5,6, Fudi Wang3, Xinchun Chen1,2,9

1Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Guangdong Medical College, Shenzhen, China

2Shenzhen Key Laboratory of Infection and Immunity, Shenzhen University School of Medicine, Shenzhen, China

3Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Zhejiang University, Hangzhou, China

4Department of Infectious Diseases and Immunology, Sydney Medical School, the University of Sydney, Sydney, NSW, Australia

5Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA

6Howard Hughes Medical Institute, Chevy Chase, MD, USA

7Department of Immunology, Bengbu Medical College, Bengbu, China

8MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

9Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

*These authors contributed equally to this work

Correspondence to:

Fudi Wang, e-mail: [email protected]

Xinchun Chen, e-mail: [email protected]

Keywords: xCT, tuberculosis, inflammatory, immune, macrophage

Received: January 26, 2016     Accepted: March 31, 2016     Published: April 27, 2016


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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