PDF(Pubmed)
Abstract：
Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMCs) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMCs, most monocytes/macrophages became foamy cells that overproduced NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMCs were exposed to Mtb H37Ra, a small subset of macrophages captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFNγ. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria, degraded them, markedly activated caspase-1 and elicited a potent IFNγ/cytotoxic response. In rabbits immunized with the same bacteria, fluvastatin increased the tuberculin test response. We conclude that statins may enhance macrophage efficacy to control Mtb, with the help of adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis.
摘要：
胆固醇生物合成抑制剂（他汀类药物）保护高胆固醇血症患者免受发展为活动性结核病，表明这些药物可以帮助宿主在疾病的初始阶段控制病原体。这项工作研究了氟伐他汀对健康外周血单个核细胞（PBMC）对灭活的结核分枝杆菌（Mtb）H37Ra的早期反应的影响。我们发现在氟伐他汀治疗的PBMC中，大多数单核细胞/巨噬细胞成为泡沫细胞，在没有免疫刺激的情况下过度产生NLRP3炎性体成分，证明重要的胆固醇代谢/免疫连接。当氟伐他汀处理和未处理的PBMC暴露于MtbH37Ra时，一小部分巨噬细胞捕获了大量的杆菌并死亡，将细菌集中在坏死区域。在未经治疗的氟伐他汀培养物中，大多数剩余的巨噬细胞成为上皮样细胞,这些细胞在肉芽肿结构中分离出这些细胞死亡区域,这些肉芽肿结构几乎不产生IFNγ.相比之下,在氟伐他汀治疗的培养物中，泡沫巨噬细胞包围着积聚的细菌，贬低他们，显着激活caspase-1并引起有效的IFNγ/细胞毒性反应。在用相同细菌免疫的兔子中，氟伐他汀增加结核菌素试验反应。我们得出的结论是，他汀类药物可能会增强巨噬细胞的功效以控制Mtb，在适应性免疫的帮助下，提供了一个有希望的工具，在替代治疗结核病的设计。
