Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China.
Department of Basic Research, Guangzhou National Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China.
ACS Infect Dis. 2024 Oct 11;10(10):3650-3663. doi: 10.1021/acsinfecdis.4c00529. Epub 2024 Oct 3.
Cholesterol is a key carbon source for (Mtb) survival and persistence within macrophages. However, little is known about the role of cholesterol metabolism by Mtb in host-Mtb interplay. Here, we report the immune suppression mediated by Mtb's cholesterol metabolites. Conducting the cholesterol metabolic profiling and loss-of-function experiments, we show that the cholesterol oxidation products catalyzed by a thiolase FadA5 from Mtb H37Ra, 4-androstenedione (AD), and its derivant 1,4-androstenedione (ADD) inhibit the expression of pro-inflammatory cytokines and thus promote bacterial survival in bone marrow-derived macrophages (BMDMs). Our time-resolved fluorescence resonance energy transfer (TR-FRET)-based screening further identifies the nuclear receptor LXRα as the target of ADD. Activation of LXRα via ADD impedes the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling and reduces cholesterol accumulation in lipid rafts upon TLR4 simulation, thereby compromising the inflammatory responses. Our findings provide the evidence that Mtb could suppress the host immunity through its cholesterol metabolic enzyme and products, which are potential targets for screening novel anti-tuberculosis (TB) agents.
胆固醇是结核分枝杆菌（Mtb）在巨噬细胞内存活和持续存在的关键碳源。然而，对于 Mtb 胆固醇代谢在宿主-分枝杆菌相互作用中的作用知之甚少。在这里，我们报告了 Mtb 胆固醇代谢物介导的免疫抑制作用。通过进行胆固醇代谢谱分析和功能丧失实验，我们表明，来自结核分枝杆菌 H37Ra 的硫酯酶 FadA5 催化的胆固醇氧化产物，雄烯二酮（AD）及其衍生物 1,4-雄烯二酮（ADD）抑制促炎细胞因子的表达，从而促进骨髓来源的巨噬细胞（BMDMs）中的细菌存活。我们基于时间分辨荧光共振能量转移（TR-FRET）的筛选进一步确定了核受体 LXRα 是 ADD 的靶标。ADD 通过激活 LXRα 来干扰核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路，并减少 TLR4 刺激时脂筏中的胆固醇积累，从而损害炎症反应。我们的研究结果提供了证据表明，Mtb 可以通过其胆固醇代谢酶和产物来抑制宿主免疫，这些酶和产物是筛选新型抗结核（TB）药物的潜在靶点。
