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 1

Mice treated with FTY720 30 days after infection have decreased survival and an increase in C.

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Mice treated with FTY720 30 days after infection have decreased survival...
neoformansgrowth in granulomas. (A) Mice were infected for 30 days with C. neoformans Δgcs1 before daily compound oral administration and survival of mice was monitored. All compounds were given at a dose of 1 mg/kg/day. Survival curves were compared using the log-rank (Mantel-Cox) test. For FTY720, n = 16 mice; BAF312, n = 14 mice; and vehicle control (H2O), n = 14 mice. *P = 0.0025. (B and C) After 50 days of daily compound administration or when mice lost more than 20% body weight, mice were sacrificed and organs were analyzed for CFUs. For FTY720, n = 11 mice; BAF312, n = 11 mice; and vehicle control (H2O), n = 11 mice. Organ burden was compared using 1-way ANOVA with Bonferroni’s multiple comparisons post hoc test. P values were corrected for multiplicity using the Bonferroni’s adjustment. **P = 0.0016. All error bars represent SEM. (D) After 50 days of daily compound administration, 4 lungs were isolated for histology using H&E stain (top 2 rows) and mucicarmine (bottom row). C. neoformans cells stain magenta in mucicarmine. Scale bars: 200 μm (top row), 50 μm (middle and bottom rows), and 12.5 μm (inset, white bar). The white boxes indicate the enlarged area and the black arrowheads denote the border of the granuloma.