The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice

Abstract

To evaluate the therapeutic effects of the new synthetic sphingosine-1-phosphate (S1P) receptor modulator, FTY720, we investigated how FTY720 affects the development of dextran sulfate sodium (DSS)-induced colitis and CD4 + CD62L + T cell transfer colitis. BALB/c mice were fed a chow containing 3.5% (wt/wt) DSS to induce colitis. The CD4 + CD62L + T cell transfer colitis was induced by an intraperitoneal injection of CD4 + CD62L + spleen T cells into recipient CB17 SCID mice. The FTY720 was administered by lavage at a dose of 0.3 mg/kg/day. FTY720 was effective in preventing the body weight loss in the DSS-colitis model and the CD4 + CD62L + T cell transfer model. The disease activity index, histological colitis score, and MPO activity were all significantly lower in FTY720-treated mice than in the nontreated mice. Microscopically, mucosal edema, cellular infiltration and epithelial disruption were much more moderate in the FTY720-treated mice than in the non-treated mice. In both colitis models, FTY720 prevented the infiltration of CD4 + T cells into the inflamed colonic lamina propria. In conclusion, the development of DSS-colitis and CD4 + CD62L + T cell transfer colitis were significantly attenuated by FTY720. Since FTY720 is an immunosuppressive product that does not modulate T cell functions, it could be useful in the treatment of IBD patients.

The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium

“…In addition to an increased bacterial burden, more extensive pathogen distribution, and impaired bacterial clearance, these mice exhibited higher disease activity at peak infection and greater colonic pathology at day 14 p.i. These findings are in contrast to what has been previously demonstrated in experimental models of colitis reflecting inflammatory bowel disease (11,12,14,18,36). In these instances, FTY720 had a therapeutic effect on disease by blunting immunity.…”

“…Controversy surrounds the complex mechanism of action of FTY720 in vivo, and it is unclear whether it acts as an agonist, a functional antagonist, or both during the regulation of lymphocyte recirculation (21,47,52,58). FTY720 ameliorated disease in numerous preclinical models of colitis, including those induced by oxazolone (12), 2,4,6-trinitrobenzene sulfonic acid (11), dextran sulfate sodium (14), and adoptive transfer (14,18), and in interleukin-10 (IL-10)-deficient mice (36). In addition, it was therapeutically efficacious in graft-versus-host disease (24) and in studies of transplantation and MS (2,4,23).…”

Current and emerging therapeutic targets for IBD

“…Moreover, S1PR expressed in immune cells controls their egress from lymph nodes to lymph and plasma and S1PR agonists cause lymphopenia in blood and thoracic duct lymph by cell sequestration in lymph nodes 69 . Inhibition of lymphocyte recirculation via S1PR signalling suppressed experimental colitis and development of colitis associated neoplasias in mice [70][71][72] . Thus, S1P receptor agonists (ozanimod (formerly known as RPC1063), APD334 and MT 1303) have been tested in human ulcerative colitis.…”

Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

“…Although in the majority of these studies other molecular targets than IRs were found to mediate the anti-inflammatory action of imidazoline drugs, the intriguing hypothesis of Molderings et al (2007a, b) that I1-IRs may belong to the family of S1P receptors and represent mixtures of homo and/or heterodimers of S1P1-3 receptors suggests that also pharmacological modulation of I1-IRs may result in reduced inflammation. Namely, it is well-established that S1P1-3 receptors are essential for immune cell trafficking and lymphocyte egress from lymphoid organs (Aoki et al 2016), and S1P receptor modulators ameliorate the severity of inflammation in different diseases, including colitis (Daniel et al 2007; Deguchi et al 2006;Snider et al 2009). Therefore, it can be hypothesized that I1-IR ligands may interfere with normal S1P signaling, which in turn might induce anti-inflammatory action.…”

“…Because S1P receptors have pivotal role in the regulation of immune cell trafficking (reviewed e.g. by Aoki et al 2016;Chi 2011;Cyster and Schwab 2012), it can be speculated that I1-IR ligands may have immunomodulatory properties, similarly to the S1P receptor modulator FTY720, which has potent antiinflammatory effect in various clinical and preclinical inflammatory conditions, including dextran sulfate sodium (DSS)-and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-evoked murine colitis (Daniel et al 2007;Deguchi et al 2006). In short, these data suggest that imidazoline drugs, such as moxonidine and rilmenidine, may have beneficial (and yet unrecognized) effects in patients with inflammatory diseases, including colitis.…”