FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages
FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages
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DOI：
10.1172/jci136068
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发表时间：
2020-09-01
影响因子：
15.9
通讯作者：
Del Poeta, Maurizio
中科院分区：
文献类型：
--
作者：
Bryan, Arielle M.;You, Jeehyun Karen;Del Poeta, Maurizio
FTY 720是一种治疗复发缓解型多发性硬化症（MS）的药物。它是鞘氨醇-1-磷酸（S1 P）的类似物，靶向S1 P受体1、3、4和5。最近的报告表明长期暴露于FTY 720和隐球菌感染病例之间存在关联。在这里，我们研究了FTY 720及其衍生物BAF 312在隐球菌感染小鼠模型中的作用，它们仅靶向S1 P受体1和5。我们发现用FTY 720治疗，而不是用BAF 312治疗，导致小鼠隐球菌肉芽肿的存活率降低和器官负荷增加。FTY 720和BAF 312均引起血液和肺中的CD 4（+）和CD 8（+）T细胞的严重耗竭，但仅FTY 720治疗导致隐球菌再活化。用FTY 720处理，而不是用BAF 312处理，与肉芽肿部位的巨噬细胞的解体和M2极化相关。在细胞系统中，FTY 720减少巨噬细胞的吞噬作用和活性氧的产生，这是S1 pr 3（-/-）敲除巨噬细胞中重现的表型。我们的研究结果表明，FTY 720通过S1 P受体3介导的机制从肉芽肿中重新激活隐球菌病，并支持开发更特异性的受体调节剂用于MS治疗的基本原理。
FTY720 is a treatment for relapsing remitting multiple sclerosis (MS). It is an analog of sphingosine-1-phosphate (S1P) and targets S1P receptors 1, 3, 4, and 5. Recent reports indicate an association between long-term exposure to FTY720 and cases of cryptococcal infection. Here, we studied the effect of FTY720 and its derivative, BAF312, which only target S1P receptors 1 and 5, in a mouse model of cryptococcal infection. We found that treatment with FTY720, but not with BAF312, led to decreased survival and increased organ burden in mouse cryptococcal granulomas. Both FTY720 and BAF312 caused a profound CD4(+) and CD8(+) T cell depletion in blood and lungs but only treatment with FTY720 led to cryptococcal reactivation. Treatment with FTY720, but not with BAF312, was associated with disorganization of macrophages and with M2 polarization at the granuloma site. In a cell system, FTY720 decreased phagocytosis and production of reactive oxygen species by macrophages, a phenotype recapitulated in the S1pr3(-/-) knockout macrophages. Our results suggest that FTY720 reactivates cryptococcosis from the granuloma through a S1P receptor 3-mediated mechanism and support the rationale for development of more-specific receptor modulators for therapeutic use of MS.