Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine‐1‐phosphate lyase inhibitor

Shirakabe, Kazuhiko; Higashiyama, Masaaki; Furuhashi, Hirotaka; Takajo, Takeshi; Maruta, Koji; Okada, Yoshikiyo; Kurihara, Chie; Watanabe, Chikako; Komoto, Shunsuke; Tomita, Kengo; Nagao, Shigeaki; Miura, Soichiro; Saruta, Masayuki; Hokari, Ryota

doi:10.1111/jgh.14092

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…In a TNF-overproducing model of Crohn-like ileitis (TNF∆ARE), S1P-lyase inhibitors altered the S1P gradient and attenuated ileitis [ 24 ]. In addition, an S1P-lyase inhibitor ameliorated DSS-induced colitis [ 123 ]. However, other studies in mice show that a deficit of intestinal S1P-lyase worsened disease [ 124 ].…”

Section: Future Directions For S1p Pathway Targetingmentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Pérez-Jeldres

Álvarez-Lobos

Rivera–Nieves

2021

Drugs

111

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Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

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Section: Future Directions For S1p Pathway Targetingmentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Pérez-Jeldres

Álvarez-Lobos

Rivera–Nieves

2021

Drugs

111

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“…Mice treated with FTY720 (1 mg/kg) prior to induction of acute colitis (3% DSS) demonstrated improvements to classical features of colitis, surprisingly due to elevations of S1P levels. These data may indicate an alternative role in S1PR modulation dependent on the timing of treatment and disease onset [84]. Balb/c mice in the acute model of colitis (3.5% DSS) treated with FTY720 (0.3 mg/kg) exhibited decreased neutrophil and CD4+ T cell infiltration to the colon [85].…”

Section: In Vivomentioning

confidence: 88%

Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer

Espinoza,

Snider

2024

Cancers

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Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed.

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“…Thoracic duct lymphocytes (TDLs) were collected from the donor rats to obtain the lymphocytes, 15,16 which is mainly composed of gut‐tropic lymphocytes 17 . TDLs were fluorescently stained with carboxyfluorescein diacetate succinimidyl ester (CFSE, Thermo Fisher Scientific) before use 18 …”

Section: Methodsmentioning

confidence: 99%

Deoxycholic acid enhancement of lymphocyte migration through direct interaction with the intestinal vascular endothelium

Shibuya

Higashiyama²,

Akita

et al. 2021

J of Gastro and Hepatol

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Background and Aim The small intestine plays a central role in gut immunity, and enhanced lymphocyte migration is involved in the pathophysiology of various enteropathy. Bile acid (BA) is closely related to lipid metabolism and gut microbiota and essential for gut homeostasis. However, the effects of BA on gut immunity have not been studied in detail, especially on the small intestine and lymphocyte migration. Therefore, we aimed to investigate the effect of BA on small intestinal lymphocyte microcirculation. Methods The effect of deoxycholic acid (DCA), taurocholic acid (tCA), or cholic acid (CA) on the indomethacin (IND)‐induced small intestinal enteropathy in mice was investigated. Lymphocyte movements were evaluated after exposure to BA using intravital microscopy. The effects of BA on surface expression of adhesion molecules on the vascular endothelium and lymphocytes through BA receptors were examined in vitro. Results IND‐induced small intestinal enteropathy was histologically aggravated by DCA treatment alone. The expression of adhesion molecules ICAM‐1 and VCAM‐1 was significantly enhanced by DCA. Exposure to DCA increased lymphocyte adhesion in the microvessels of the ileum, which was partially blocked by anti‐α4β1 integrin antibody in vivo. The expression of ICAM‐1 and VCAM‐1 was significantly enhanced by DCA in vitro, which was partially suppressed by the sphingosine‐1‐phosphate receptor 2 (S1PR2) antagonist. The S1PR2 antagonist significantly ameliorated IND‐induced and DCA‐exaggerated small intestinal injury. Conclusion DCA exacerbated IND‐induced small intestinal enteropathy. DCA directly acts on the vascular endothelium and enhances the expression levels of adhesion molecules partially via S1PR2, leading to enhanced small intestinal lymphocyte migration.

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Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine‐1‐phosphate lyase inhibitor

Cited by 5 publications

References 31 publications

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer

Deoxycholic acid enhancement of lymphocyte migration through direct interaction with the intestinal vascular endothelium

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