FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages
Arielle M. Bryan, … , Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
Arielle M. Bryan, … , Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(9):4546-4560. https://doi.org/10.1172/JCI136068.
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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 6

Treatment with FTY720 but not BAF312 affects M2 macrophage polarization in the granuloma structure.

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Treatment with FTY720 but not BAF312 affects M2 macrophage polarization ...
(A) Mice were infected for 30 days with C. neoformans Δgcs1 before FTY720, BAF312, or vehicle control (H2O) administration. At day 60 after compound administration, lungs were processed for CD38 (gray) and EGR2 (magenta) immunohistochemistry to assess for M1 and M2 macrophage polarization, respectively. Scale bars: 200 μm (top), 50 μm (bottom). (B) The relative intensity of CD38 and EGR2 staining inside versus outside the bounds of the granuloma, as delineated by the collagen deposition seen in VVG of Figure 5, was quantified using Image J software, n = 3. All error bars represent SEM. Comparisons were done with 2-way ANOVA with Bonferroni’s multiple comparisons post hoc test. P value was corrected for multiplicity using Bonferroni’s adjustment. *P = 0.0393, **P = 0.0084, ****P < 0.0001 compared with the control. ####P < 0.0001 compared with BAF312.