Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, USA.
FirstString Research Inc., Mount Pleasant, South Carolina, USA.
J Clin Invest. 2020 Sep 1;130(9):4546-4560. doi: 10.1172/JCI136068.
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.
FTY720 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 (S1P) 的类似物，作用于 S1P 受体 1、3、4 和 5。最近的报告表明，长期暴露于 FTY720 与隐球菌感染病例之间存在关联。在这里，我们研究了 FTY720 及其衍生物 BAF312 在隐球菌感染小鼠模型中的作用。我们发现，FTY720 治疗而非 BAF312 治疗导致小鼠隐球菌肉芽肿中的生存率降低和器官负担增加。FTY720 和 BAF312 均可导致血液和肺部中 CD4+和 CD8+T 细胞的严重耗竭，但只有 FTY720 治疗导致隐球菌再激活。FTY720 治疗而非 BAF312 治疗与巨噬细胞的紊乱和肉芽肿部位的 M2 极化有关。在细胞系统中，FTY720 降低了巨噬细胞的吞噬作用和活性氧物质的产生，这一表型在 S1pr3-/- 基因敲除巨噬细胞中得到了重现。我们的研究结果表明，FTY720 通过 S1P 受体 3 介导的机制使隐球菌病从肉芽肿中重新激活，并支持开发更具特异性的受体调节剂用于治疗多发性硬化症的原理。
