FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages.
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 effe...
| Publicado en: | Journal of Clinical Investigation Vol. 130; no. 9; pp. 4546 - 4561 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
American Society for Clinical Investigation
Sep2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=145520537&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 145520537 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00219738 0YX jtl: Journal of Clinical Investigation issn: 00219738 maglogo: N pubinfo: dt: Sep2020 vid: 130 iid: 9 pid: 11983 pub: American Society for Clinical Investigation place: Ann Arbor, Michigan artinfo: ui: 145520537 145520537 NLM32484801 145520537 10.1172/JCI136068 NLM32484801 145520537 ppf: 4546 ppct: 15 formats: tig: atl: FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages. aug: au: Bryan, Arielle M. You, Jeehyun Karen McQuiston, Travis Lazzarini, Cristina Zhijuan Qiu Sheridan, Brian Nuesslein-Hildesheim, Barbara Del Poeta, Maurizio Qiu, Zhijuan Sheridan, Brian S affil: Department of Microbiology and Immunology, Stony Brook University, Stony Brook, New York, USA. sug: subj: Granuloma Drug Therapy Cryptococcosis Drug Therapy Cryptococcus Metabolism Macrophages Metabolism Granuloma Pathology Granuloma Metabolism Mice Cryptococcosis Pathology Animal Studies Macrophages Microbiology Male Cryptococcosis Metabolism Female Cell Line Granuloma Microbiology Human Macrophages Pathology Validation Studies Comparative Studies Evaluation Research Multicenter Studies Male Female ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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