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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.

SUBMITTER: Bryan AM

PROVIDER: S-EPMC7456236 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Bryan Arielle M AM You Jeehyun Karen JK McQuiston Travis T Lazzarini Cristina C Qiu Zhijuan Z Sheridan Brian B Nuesslein-Hildesheim Barbara B Del Poeta Maurizio M

The Journal of clinical investigation 20200901 9

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 ...[more]

PMID: 32484801

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Project description:BackgroundThe endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection.Principal findingsHere we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation.ConclusionsIn summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection.

Dataset Information

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

Publications

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

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