Myriocin enhances the clearance of M. tuberculosis by macrophages through the activation of PLIN2
Ximeng Zhang,
Guanggui Ding,
Xirui Yang,
Hailin Lu,
Yuzhong Xu,
Yunlong Hu,
Song Liu,
Huihua Zhang,
Kaisong Huang,
Guofang Deng,
Taosheng Ye,
Qing Yu,
Yi Cai,
Shuixiang Xie,
Wenfei Wang,
Xinchun Chen
Affiliations
Ximeng Zhang
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Guanggui Ding
Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
Xirui Yang
Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA
Hailin Lu
Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
Yuzhong Xu
Department of Clinical Laboratory, Shenzhen Baoan Hospital, Shenzhen, China
Yunlong Hu
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Song Liu
Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
Huihua Zhang
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Kaisong Huang
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
Guofang Deng
National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, China
Taosheng Ye
National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, China
Qing Yu
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Yi Cai
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
Shuixiang Xie
Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
Wenfei Wang
National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, China
Xinchun Chen
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen, China
ABSTRACT Myriocin is an inhibitor of de novo synthesis of sphingolipids and ceramides. In this research, we showed myriocin could significantly reduce Mtb burden and histopathological inflammation in mice. However, the underlying mechanism remains unclear. RNA-seq analysis revealed a significant increase in gene expression of PLIN2/CD36/CERT1 after myriocin treatment. The reduced bactericidal burden was only reversed after silencing the lipid droplets (LDs) surface protein PLIN2. This suggests that myriocin enhances the ability of macrophages to clear Mtb depending on the PLIN2 gene, which is part of the PPARγ pathway. Indeed, we observed a significant increase in the number of LDs following myriocin treatment.IMPORTANCEMycobacterium tuberculosis has the ability to reprogram host cell lipid metabolism and alter the antimicrobial functions of infected macrophages. The sphingolipids, such as ceramides, are the primary host lipids utilized by the bacteria, making the sphingomyelinase/ceramide system critical in Mtb infections. Surprisingly, the antimicrobial effect of myriocin was found to be independent of its role in reducing ceramides, but instead, it depends on the lipid droplets surface protein PLIN2. Our findings provide a novel mechanism for how myriocin enhances Mtb clearance in macrophages.
