PDF(Pubmed)
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.
摘要：
Myriocin是鞘脂和神经酰胺从头合成的抑制剂。在这项研究中,我们发现，Myriocin可以显著减轻小鼠的Mtb负荷和组织病理学炎症。然而,潜在机制尚不清楚.RNA-seq分析显示，在肉豆蔻素治疗后，PLIN2/CD36/CERT1的基因表达显着增加。减少的杀菌负担仅在沉默脂滴（LD）表面蛋白PLIN2后逆转。这表明Myriocin增强了巨噬细胞清除Mtb的能力，这取决于PLIN2基因，是PPARγ途径的一部分。的确,我们观察到Myriocin治疗后LD的数量显着增加。重要结核分枝杆菌具有重新编程宿主细胞脂质代谢和改变感染巨噬细胞的抗菌功能的能力。鞘脂，如神经酰胺，是细菌利用的主要宿主脂质，使鞘磷脂酶/神经酰胺系统在Mtb感染中至关重要。令人惊讶的是,发现Myriocin的抗菌作用独立于其减少神经酰胺的作用，但相反，它取决于脂滴表面蛋白PLIN2。我们的发现为Myriocin如何增强巨噬细胞中的Mtb清除提供了新的机制。
