Myriocin enhances the clearance of M. tuberculosis by macrophages through the activation of PLIN2

• Published in: mSphere 2024-07, Vol.9 (7), p.e0025724
• Main Authors: Zhang, Ximeng, Ding, Guanggui, Yang, Xirui, Lu, Hailin, Xu, Yuzhong, Hu, Yunlong, Liu, Song, Zhang, Huihua, Huang, Kaisong, Deng, Guofang, Ye, Taosheng, Yu, Qing, Cai, Yi, Xie, Shuixiang, Wang, Wenfei, Chen, Xinchun
• Format: Article
• Language: English
• Subjects: Animals; Antimicrobial activity; Binomial distribution; CD36 antigen; Cell activation; Cell culture; Ceramide; Drug resistance; Fatty Acids, Monounsaturated - metabolism; Fatty Acids, Monounsaturated - pharmacology; Female; Gene expression; host-directed therapy; Host-Microbial Interactions; Infections; Lipid Droplets - drug effects; Lipid Droplets - metabolism; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Macrophages; Macrophages - drug effects; Macrophages - microbiology; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; myriocin; Pathology; Penicillin; Perilipin-2 - genetics; Perilipin-2 - metabolism; PLIN2; Proteins; Research Article; Special Series: Metabolism in Infection Biology; Sphingolipids; Sphingomyelin phosphodiesterase; Tuberculosis; Tuberculosis - drug therapy; Tuberculosis - immunology; Tuberculosis - microbiology; Tumor necrosis factor-TNF
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/msphere.00257-24

Myriocin is an inhibitor of 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.IMPORTANCE 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.