FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages
Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian Sheridan, Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian Sheridan, Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
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Research Article Immunology Infectious disease

FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages

Abstract

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.

Authors

Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian Sheridan, Barbara Nuesslein-Hildesheim, Maurizio Del Poeta

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Figure 8

S1P/S1PR3 signaling is required for phagocytosis, ROS production, and intracellular killing of C. neoformans Δgcs1.

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S1P/S1PR3 signaling is required for phagocytosis, ROS production, and in...
(A) Primary alveolar macrophages isolated from WT (n = 8) and S1PR3 deficient (n = 6) mice were coincubated with opsonized C. neoformans Δgcs1 and phagocytic index was calculated by microscopic observation. Experiment was conducted 3 times. (B) Phagocytic index for primary alveolar macrophages isolated from mice of indicated genotype (n = 5 each) with and without S1P supplementation were calculated as in A. Experiment was conducted 3 times. (C) Primary alveolar macrophages isolated from mice of indicated genotype (n = 3) with and without S1P supplementation were coincubated with opsonized C. neoformans Δgcs1. After incubation, culture media were plated onto YPD agar. Percentage of killing was calculated as the difference in CFUs of Δgcs1 incubated with or without macrophages. Experiment was conducted 5 times. (D) Primary alveolar macrophages of the indicated genotype (n = 3) were analyzed for ROS production after coincubation with opsonized C. neoformans Δgcs1. Experiment was conducted 5 times. All error bars represent SEM and statistical comparisons were done using 2-sided Student’s t test (*P = 0.0378, **P = 0.0222) or 1-way ANOVA with Bonferroni’s multiple comparisons post hoc test. P values were corrected for multiplicity using the Bonferroni’s adjustment (***P < 0.001, ****P < 0.0001, compared with control).