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CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR11 Leukocyte Trafficking in Mice with Colitis

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CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR11 Leukocyte Trafficking in Mice with Colitis 1521-0111/92/5/502–509$25.00 https://doi.org/10.1124/mol.117.108381 MOLECULAR PHARMACOLOGY Mol Pharmacol 92:502–509, November 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics E6130, a Novel CX3C Chemokine Receptor 1 (CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR11 Leukocyte Trafficking in Mice with Colitis Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi, and Toshio Imai Eisai Co., Ltd., Tsukuba Research Laboratories, Ibaraki (H.W., T.Y., Y.K.) and KAN Research Institute Inc., Hyogo (T.I.), Japan Received February 1, 2017; accepted August 16, 2017 Downloaded from ABSTRACT The chemokine fractalkine (CX3C chemokine ligand 1; CX3CL1) (IC50 4.9 nM), most likely via E6130-induced down-regulation of and its receptor CX3CR1 are involved in the pathogenesis of CX3CR1 on the cell surface. E6130 had agonistic activity via several diseases, including inflammatory bowel diseases such as CX3CR1 with respect to guanosine 59-3-O-(thio)triphosphate Crohn’s disease and ulcerative colitis, rheumatoid arthritis, hepa- binding in CX3CR1-expressing Chinese hamster ovary K1 titis, myositis, multiple sclerosis, renal ischemia, and athero- (CHO-K1) membrane and had no antagonistic activity. Orally sclerosis. There are no orally available agents that modulate the administered E6130 ameliorated several inflammatory bowel molpharm.aspetjournals.org fractalkine/CX3CR1 axis. [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl) disease–related parameters in a murine CD41CD45RBhigh benzyl]-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}- T-cell-transfer colitis model and a murine oxazolone-induced 4-methylpyrrolidin-3-yl]acetic acid (2S)-hydroxy(phenyl)acetate colitis model. In the CD41CD45RBhigh T-cell transfer model, (E6130) is an orally available highly selective modulator of E6130 inhibited the migration of CX3CR11 immune cells and CX3CR1 that may be effective for treatment of inflammatory decreased the number of these cells in the gut mucosal bowel disease. We found that E6130 inhibited the fractalkine- membrane. These results suggest that E6130 is a promising induced chemotaxis of human peripheral blood natural killer cells therapeutic agent for treatment of inflammatory bowel disease. at ASPET Journals on October 6, 2021 Introduction superfamily cellular adhesion molecules (Charo and Ransoh- off, 2006; Thomas and Baumgart, 2012). Inflammatory bowel disease is a group of idiopathic, chronic Chemokines and their receptors are also important means intestinal inflammatory diseases that primarily includes two of orchestrating tissue-specific and cell type–selective leuko- ’ distinct conditions: Crohn s disease and ulcerative colitis, which cyte trafficking (Nishimura et al., 2009). For example, frac- are both the result of inappropriate immune responses to talkine (also known as CX3C motif ligand 1; CX3CL1) is a antigens produced by commensal microorganisms. Although chemokine prominently expressed by epithelial and endothe- the signs of Crohn’s disease and ulcerative colitis manifest lial cells that functions as both an adhesion molecule and a primarily in the gastrointestinal tract, these diseases affect the chemotactic factor (Bazan et al., 1997; Nishimura et al., 2002). entire human body (Baumgart and Sandborn, 2007). Therapeu- Fractalkine binds to its sole receptor, CX3C chemokine tic treatments that inhibit cytokines are currently in widespread receptor 1 (CX3CR1), which is expressed on the surfaces of clinical use; however, the serious adverse events and lack of long- monocytes, macrophages, dendritic cells, microglia, natural term efficacy of these treatments remain serious concerns. killer (NK) cells, and cytotoxic effector T-cells that contribute Infiltration of leukocytes from the peripheral circulation to the development of chronic inflammation (Imai et al., 1997; into tissues such as the gut mucosa is an important aspect of Yoshie et al., 2001). In patients with inflammatory bowel immune surveillance. To enter the mucosal tissue from the disease, the expression of fractalkine by intestinal epithelial blood, leukocytes must cross the endothelial barrier. They do cells and microvascular cells and of CX3CR1 by peripheral this by interacting with cytokine or other proinflammatory blood T-cells increases with the level of disease activity. Thus, stimuli-activated endothelial cells via either leukocyte cell- the fractalkine/CX3CR1 axis appears to be directly involved in surface chemokine receptors (and their respective endothelial the pathogenesis of inflammatory bowel disease (Brand et al., and mucosal ligands) or via integrins and immunoglobulin 2006; Kobayashi et al., 2007; Sans et al., 2007). Here, we characterized [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl)- This work was funded by Eisai Co., Ltd. benzyl]-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}- https://doi.org/10.1124/mol.117.108381. 4-methylpyrrolidin-3-yl]acetic acid (2S)-hydroxy(phenyl)acetate ABBREVIATIONS: ANOVA, analysis of variance; CCR, CC chemokine receptor; CHO-K1, Chinese hamster ovary K1; CX3CR1, CX3C chemokine receptor 1; E6130, [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl)benzyl]-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3- yl]acetic acid (2S)-hydroxy(phenyl)acetate; GPCR, G-protein coupled receptor; LSD, least significant difference; MCP-1, monocyte chemo- attractant protein-1; MFI, mean fluorescence intensity; NK cells, natural killer cells; PBS, phosphate-buffered saline; RLU, relative light units; SCID, severe combined immunodeficiency; [35S]GTPgS, guanosine 59-O-(3-[35S]thio)triphosphate. 502 Characterization of a Modulator of Chemokine Receptor CX3CR1 503 (E6130), a previously identified novel modulator of CX3CR1. We After incubation for 10 minutes on ice with 7-amino actinomycin D found that E6130 inhibited fractalkine-induced chemotaxis (Sigma-Aldrich) to discriminate dead cells, the fluorescence intensity and induced down regulation of CX3CR1 on the cell surface in of the stained cells was determined by using a FACSCanto cell NK cells from human peripheral blood. E6130 also prevented analyzer (Becton Dickinson, Franklin Lakes, NJ). Loss of CX3CR1 the trafficking of CX3CR1-expressing leukocytes into colonic staining on the cell surface was assumed to represent the induction of 1 high down-regulation of CX3CR1 on the cell surface. The mean fluorescence tissue in a murine CD4 CD45RB T cell–transfer colitis 1 intensity (MFI) of the CX3CR1 cell population among the total NK – model, and it ameliorated other inflammatory bowel disease cell population was also determined by using a FACSCanto cell 1 high related parameters in both the murine CD4 CD45RB analyzer. The percentage MFI of the control was determined by using T-cell-transfer colitis model and a murine oxazolone-induced the following formula: colitis model. Together, these results suggest that E6130 is a À Á promising agent for treating the inflammatory bowel disease. % 5 2 MFI of control ÀMFItest well MFIbackground well Á MFIcontrol well 2 MFIbackground well  100; Materials and Methods where “test well” refers to wells containing E6130 and staining antibodies, “control well” refers to wells containing staining antibodies – Animals. BALB/c mice (female, 7 10 weeks old) were obtained only, and “background well” refers to wells containing neither the from Charles River Laboratories Japan (Tokyo, Japan). Severe staining antibodies nor E6130. combined immunodeficiency (SCID) mice (female, 6 weeks old) were Isolation of NK Cells from Human Peripheral Blood. An Downloaded from obtained from CLEA Japan (Tokyo, Japan). The mice were group- aliquot (25 ml) of human peripheral blood was added to a plastic 6 housed under controlled conditions (temperature, 22 3°C; humidity, centrifugation tube containing 100 U of heparin sodium (Ajinomoto, 6 55% 5%; 12-hour light/dark cycle) with ad libitum access to water Tokyo, Japan). An aliquot (8 ml) of physiologic saline containing 6% and standard pelleted food. All animal experiments were approved by dextran (Nacalai Tesque, Kyoto, Japan) was added to the tube, and the the Committee for the Welfare of Laboratory Animals, Eisai Co. Ltd. mixture was allowed to stand at room temperature for 30 minutes to Test Compound and Reagents. E6130 was synthesized by Eisai allow sedimentation of the erythrocytes. The supernatant was trans- molpharm.aspetjournals.org Co., Ltd. at its plant located in Kashima, Japan (Yoshida et al., 2013). ferred to another plastic centrifugation tube, mixed with an equivalent The chemical structure of E6130 is shown in Fig. 1. Oxazolone was volume of PBS, and then centrifuged at 1800 rpm for 7 minutes at purchased from Sigma-Aldrich (St. Louis, MO). Recombinant human room temperature. The resultant hemocyte fraction was suspended in fractalkine was purchased from R&D Systems (Minneapolis, MN). 4 ml of PBS, and the suspension was superposed on 4 ml of Ficoll- CX3CR1 Down-Regulation Assay. Assay medium (RPMI 1640 Paque Plus (GE Healthcare Life Sciences, Tokyo, Japan). medium containing 10% fetal bovine serum, 80 ml/well) and E6130 After centrifugation of the suspension at 2200 rpm for 30 minutes at (10 ml/well) were added to each well of a 96-well culture plate. room temperature, the cells in the intermediate layer (peripheral Written informed consent was obtained from each subject before blood mononuclear cells) were collected, suspended in PBS, and blood draw. Human peripheral blood was drawn from the forearm centrifuged at 1800 rpm for 7 minutes. The
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