FTY720 ameliorates experimental autoimmune neuritis by inhibition of lymphocyte and monocyte infiltration into peripheral nerves

Zhang, Zhiren; Fauser, U.; Schluesener, Hermann J.

doi:10.1016/j.expneurol.2007.12.025

Cited by 67 publications

(61 citation statements)

References 28 publications

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“…This observation, along with our data utilizing BAF312, suggests that monocyte expression of S1P 3 is not solely responsible for monocyte trafficking. Although other groups have mentioned that they did not observe reductions in circulating monocytes with FTY720 treatment (15,18,20,36,37), monocytes were not the focus of these studies, monocyte levels were assessed in a disease model in which monocytes are already affected (18), or surface markers were used that are not specific for monocytes (36). Our studies, however, provide an in-depth analysis of the effects of FTY720 and BAF312 on monocytes at several doses under multiple conditions and were consistent in both mice and rats.…”

Section: Discussionmentioning

confidence: 91%

“…A reduction in the number of macrophages has been observed in several tissues of FTY720-treated mice, including the following: atherosclerotic plaques in ApoE-deficient mice (18), peritoneal cavity with thioglycolate-induced peritonitis (10), peripheral nerves in experimental autoimmune neuritis (15), CNS in EAE (16), renal glomeruli in experimental mesangioproliferative glomerulonephritis (17), and heart allografts (19). However, no mechanism has been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…The role of S1P receptors on monocytes in vivo is less clear. Several reports suggest that monocyte trafficking may be restricted by modulation of S1P receptors based on reduced numbers of macrophages in tissue, such as the following: the peritoneal cavity following thioglycolate-induced peritonitis (10), peripheral nerves in experimental autoimmune neuritis (15), the CNS in experimental autoimmune encephalomyelitis (EAE) (16), renal glomeruli in experimental mesangioproliferative glomerulonephritis (17), atherosclerotic plaques (18), and heart allografts (19). However, an effect on circulating monocytes has not been reported.…”

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confidence: 99%

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Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Lewis

Haxhinasto

Anderson

et al. 2013

The Journal of Immunology

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Sphingosine-1-phosphate (S1P) receptors are critical for lymphocyte egress from secondary lymphoid organs, and S1P receptor modulators suppress lymphocyte circulation. However, the role of S1P receptors on monocytes is less clear. To elucidate this, we systematically evaluated monocytes in rats and mice, both in naive and inflammatory conditions, with S1P receptor modulators FTY720 and BAF312. We demonstrate that S1P receptor modulators reduce circulating monocytes in a similar time course as lymphocytes. Furthermore, total monocyte numbers were increased in the spleen and bone marrow, suggesting that S1P receptor modulation restricts egress from hematopoietic organs. Monocytes treated ex vivo with FTY720 had reduced CD40 expression and TNF-α production, suggesting a direct effect on monocyte activation. Similar reductions in protein expression and cytokine production were also found in vivo. Suppression of experimental autoimmune encephalomyelitis in mice and rats by FTY720 correlated with reduced numbers of lymphocytes and monocytes. These effects on monocytes were independent of S1P3, as treatment with BAF312, a S1P1,4,5 modulator, led to similar results. These data reveal a novel role for S1P receptors on monocytes and offer additional insights on the mechanism of action of S1P receptor modulators in disease.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Lewis

Haxhinasto

Anderson

et al. 2013

The Journal of Immunology

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“…In regard to the peripheral nervous system (PNS), a previous report showed that fingolimod ameliorates disease conditions in animal models of experimental autoimmune neuritis (Zhang, Zhang, Fauser, & Schluesener, 2008, 2009; Zhang, Zhang, & Schluesener, 2009) and spontaneous autoimmune polyneuropathy (Kim et al., 2009). These studies demonstrated that the number of infiltrating Th17 cells was decreased in peripheral nerves, whereas the number was increased in lymph nodes, suggesting that the therapeutic effect of fingolimod in experimental autoimmune neuritis has a similar mechanism as in MS patients.…”

Section: Discussionmentioning

confidence: 99%

Fingolimod promotes blood–nerve barrier properties in vitro

et al. 2018

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ObjectiveThe main effect of fingolimod is thought to be functional antagonism of lymphocytic S1P1 receptors and the prevention of lymphocyte egress from lymphoid tissues, thereby reducing lymphocyte infiltration into the nervous system. However, a growing number of reports suggest that fingolimod also has a direct effect on several cell types in the nervous system. Although we previously reported that fingolimod enhances blood–brain barrier (BBB) functions, there have been no investigations regarding the blood–nerve barrier (BNB). In this study, we examine how fingolimod affects the BNB.MethodsAn immortalized human peripheral nerve microvascular endothelial cell line (HPnMEC) was used to evaluate BNB barrier properties. We examined tight junction proteins and barrier functions of HPnMECs in conditioned medium with or without fingolimod‐phosphate and blood sera from patients with typical chronic inflammatory demyelinating polyneuropathy (CIDP).ResultsIncubation with fingolimod‐phosphate increased levels of claudin‐5 mRNA and protein as well as TEER values in HPnMECs. Conversely, typical CIDP sera decreased claudin‐5 mRNA/protein levels and TEER values in HPnMECs; however, pretreatment with fingolimod‐phosphate inhibited the effects of the typical CIDP sera.ConclusionsFingolimod‐phosphate directly modifies the BNB and enhances barrier properties. This mechanism may be a viable therapeutic target for CIDP, and fingolimod may be useful in patients with typical CIDP who have severe barrier disruption.

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“…3,[26][27][28][29] FTY720 reduces macrophage infiltration into sites of inflammation in many inflammatory disease models. [30][31][32][33] The mechanism of action of FTY720 may involve its effects on endothelial cells to reduce monocyte migration. 34 This study shows that the S1P 1 -selective agonist CYM inhibited aGVHD by reducing macrophage infiltration at GVHD sites.…”

Section: Introductionmentioning

confidence: 99%

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cheng

Lin

et al. 2014

Cell Mol Immunol

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FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P 1 -selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P 1 -selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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FTY720 ameliorates experimental autoimmune neuritis by inhibition of lymphocyte and monocyte infiltration into peripheral nerves

Cited by 67 publications

References 28 publications

Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Fingolimod promotes blood–nerve barrier properties in vitro

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

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