The Eph/ephrin system symphony of gut inflammation

Pharmacological Research - Tập 197 - Trang 106976 - 2023
Peishan Qiu1,2, Daojiang Li3, Cong Xiao1,2, Fei Xu1,2, Xiaoyu Chen1,2, Ying Chang1,2, Lan Liu1,2, Lei Zhang4, Qiu Zhao1,2, Yuhua Chen1,2
1Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
2Hubei Clinical Center & Key Lab of Intestinal & Colorectal Diseases, Wuhan 430071, China
3Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

Tài liệu tham khảo

Spiller, 2009, Infection, inflammation, and the irritable bowel syndrome, Digestive Liver Dis., 41, 844, 10.1016/j.dld.2009.07.007 Karlinger, 2000, The epidemiology and the pathogenesis of inflammatory bowel disease, Eur. J. Radiology, 35, 154, 10.1016/S0720-048X(00)00238-2 Elhag, 2022, Inflammatory bowel disease treatments and predictive biomarkers of therapeutic response, 23, 6966 Populin, 2021, Neuronal regulation of the gut immune system and neuromodulation for treating inflammatory bowel disease, FASEB BIOADVANCES, 3, 953, 10.1096/fba.2021-00070 Parrinello, 2010, EphB signaling directs peripheral nerve regeneration through Sox2-dependent schwann cell sorting, Cell, 143, 145, 10.1016/j.cell.2010.08.039 Grandi, 2019, Targeting the Eph/Ephrin system as anti-inflammatory strategy in IBD, Front Pharm., 10, 691, 10.3389/fphar.2019.00691 Nikolov, 2013, Eph/ephrin recognition and the role of Eph/ephrin clusters in signaling initiation, BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS Proteom., 1834, 2160, 10.1016/j.bbapap.2013.04.020 Herath, 2010, The role of Eph receptors and ephrin ligands in colorectal cancer, Int. J. Cancer, 126, 2003, 10.1002/ijc.25147 Hruska, 2012, Ephrin regulation of synapse formation, function and plasticity, Mol. Cell Neurosci., 50, 35, 10.1016/j.mcn.2012.03.004 White, 2014, Eph receptor and ephrin function in breast, gut, and skin epithelia, CELL Adhes. Migr., 8, 327, 10.4161/19336918.2014.970012 Slack, 2008, EphrinB2 induces tyrosine phosphorylation of NR2B via Src-family kinases during inflammatory hyperalgesia, NEUROSCIENCE, 156, 175, 10.1016/j.neuroscience.2008.07.023 Kobayashi, 2007, Involvement of EphB1 receptor/ephrinB2 ligand in neuropathic pain, SPINE, 32, 1592, 10.1097/BRS.0b013e318074d46a Liu, 2013, EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord, PAIN, 154, 2823, 10.1016/j.pain.2013.08.017 Niesler, 2021, Disorders of the enteric nervous system - a holistic view, Nat. Rev. Gastroenterol. Hepatol., 18, 393, 10.1038/s41575-020-00385-2 Sharkey, 2023, The enteric nervous system, Physiol. Rev., 103, 1487, 10.1152/physrev.00018.2022 Lomax, 2005, Plasticity of the enteric nervous system during intestinal inflammation, Neurogastroenterol. Motil., 17, 4, 10.1111/j.1365-2982.2004.00607.x Stavely, 2020, Targeting enteric neurons and plexitis for the management of inflammatory bowel disease, Curr. Drug Targets, 21, 1428, 10.2174/1389450121666200516173242 Margolis, 2011, Enteric neuronal density contributes to the severity of intestinal inflammation, GASTROENTEROLOGY, 141, 10.1053/j.gastro.2011.04.047 Brierley, 2014, Neuroplasticity and dysfunction after gastrointestinal inflammation, Nat. Rev. Gastroenterol. Hepatol., 11, 611, 10.1038/nrgastro.2014.103 Gregorieff, 2005, Wnt signaling in the intestinal epithelium: from endoderm to cancer, Genes Dev., 19, 877, 10.1101/gad.1295405 Takahashi, 2020, Stem cell signaling pathways in the small intestine, Int. J. Mol. Sci., 21, 10.3390/ijms21062032 Hafner, 2005, Ephrin-B2 is differentially expressed in the intestinal epithelium in Crohn's disease and contributes to accelerated epithelial wound healing in vitro, World J. Gastroenterol., 11, 4024, 10.3748/wjg.v11.i26.4024 Batlle, 2002, Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB, Cell, 111, 251, 10.1016/S0092-8674(02)01015-2 Clevers, 2013, SnapShot: the intestinal crypt, Cell, 152, 10.1016/j.cell.2013.02.030 Clevers, 2013, The intestinal crypt, a prototype stem cell compartment, Cell, 154, 274, 10.1016/j.cell.2013.07.004 Kosinski, 2007, Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors, Proc. Natl. Acad. Sci. USA, 104, 15418, 10.1073/pnas.0707210104 George, 2008, In vivo gene expression profiling of human intestinal epithelial cells: analysis by laser microdissection of formalin fixed tissues, BMC Genom., 9, 209, 10.1186/1471-2164-9-209 Papadakos, 2022, The EPH/Ephrin system in colorectal cancer, Int. J. Mol. Sci., 23, 10.3390/ijms23052761 Gulbransen, 2012, Activation of neuronal P2×7 receptor-pannexin-1 mediates death of enteric neurons during colitis, Nat. Med., 18, 600, 10.1038/nm.2679 Magalhães, 2021, Enteric nervous system and inflammatory bowel diseases: correlated impacts and therapeutic approaches through the P2×7 receptor, World J. Gastroenterol., 27, 7909, 10.3748/wjg.v27.i46.7909 El-Salhy, 2017, Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease, World J. Gastroenterol., 23, 5068, 10.3748/wjg.v23.i28.5068 Zhang, 2019, EphrinB2/ephB2-mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS, Faseb J., 33, 13644, 10.1096/fj.201901192R Xiong, 2018, Eph/ephrin signalling serves a bidirectional role in lipopolysaccharideinduced intestinal injury, Mol. Med Rep., 18, 2171 Wu, 2022, Downregulation of EphB2 by RNA interference attenuates glial/fibrotic scar formation and promotes axon growth, Neural Regen. Res., 17, 362, 10.4103/1673-5374.317988 Endres, 2018, Influence of commensal microbiota on the enteric nervous system and its role in neurodegenerative diseases, J. Innate Immun., 10, 172, 10.1159/000488629 Uesaka, 2015, Neuronal differentiation in schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system, J. Neurosci., 35, 9879, 10.1523/JNEUROSCI.1239-15.2015 Pearson, 1994, Structural organization and neuropeptide distributions in the equine enteric nervous-system - an immunohistochemical study using whole-mount preparations from the small-intestine, CELL TISSUE Res., 276, 523, 10.1007/BF00343949 Anetsberger, 2018, Morphological and immunohistochemical characterization of human intrinsic gastric neurons, Cells Tissues Organs, 206, 183, 10.1159/000500566 Smith, 2017, A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin, Am. J. Physiol. Gastrointest. Liver Physiol., 312, 10.1152/ajpgi.00337.2016 Neal, 2007, Mapping 5-HT inputs to enteric neurons of the guinea-pig small intestine, Neuroscience, 145, 556, 10.1016/j.neuroscience.2006.12.017 Mueller, 2011, Activity of protease-activated receptors in the human submucous plexus, GASTROENTEROLOGY, 141, 10.1053/j.gastro.2011.08.034 Mazzoni, 2021, Quantitative analysis of enteric neurons containing choline acetyltransferase and nitric oxide synthase immunoreactivities in the submucosal and myenteric plexuses of the porcine colon, CELL TISSUE Res., 383, 645, 10.1007/s00441-020-03286-7 Brehmer, 2010, Two submucosal nerve plexus in human intestines, Histochem Cell Biol., 133, 149, 10.1007/s00418-009-0657-2 Furness, 2018, The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems, Neurogastroenterology Motil., 30, 10.1111/nmo.13234 Hibberd, 2020, A novel mode of sympathetic reflex activation mediated by the enteric nervous system, Eneuro, 7, 10.1523/ENEURO.0187-20.2020 Furness, 2012, The enteric nervous system and neurogastroenterology, Nat. Rev. Gastroenterol. Hepatol., 9, 286, 10.1038/nrgastro.2012.32 Margolis, 2021, The microbiota-gut-brain axis: from motility to mood, Gastroenterology, 160, 1486, 10.1053/j.gastro.2020.10.066 Agirman, 2021, Signaling inflammation across the gut-brain axis, Science, 374, 1087, 10.1126/science.abi6087 Margolis, 2016, Enteric neuronal regulation of intestinal inflammation, Trends Neurosci., 39, 614, 10.1016/j.tins.2016.06.007 Gonzalez Acera, 2021, Dynamic, transient, and robust increase in the innervation of the inflamed mucosa in inflammatory bowel diseases, Cells, 10, 10.3390/cells10092253 Sigalet, 2010, The effects of glucagon-like peptide 2 on enteric neurons in intestinal inflammation, Neurogastroenterol. Motil., 22, 1318, 10.1111/j.1365-2982.2010.01585.x Poli, 2001, Morphological and functional alterations of the myenteric plexus in rats with TNBS-induced colitis, Neurochem. Res., 26, 1085, 10.1023/A:1012313424144 Sarnelli, 2009, Myenteric neuronal loss in rats with experimental colitis: role of tissue transglutaminase-induced apoptosis, Dig. Liver Dis.: Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver, 41, 185, 10.1016/j.dld.2008.06.004 Villanacci, 2008, Enteric nervous system abnormalities in inflammatory bowel diseases, NEUROGASTROENTEROLOGY Motil., 20, 1009, 10.1111/j.1365-2982.2008.01146.x Belkind-Gerson, 2015, Colitis induces enteric neurogenesis through a 5-HT4-dependent mechanism, Inflamm. Bowel Dis., 21, 870, 10.1097/MIB.0000000000000326 ter Beek, 2007, Substance P receptor expression in patients with inflammatory bowel disease - Determination by three different techniques, i.e., storage phosphor autoradiography, RT-PCR and immunohistochemistry, NEUROPEPTIDES, 41, 301, 10.1016/j.npep.2007.05.002 Rivera, 2011, The involvement of nitric oxide synthase neurons in enteric neuropathies, Neurogastroenterol. Motil., 23, 980, 10.1111/j.1365-2982.2011.01780.x Kono, 2004, Impaired nitric oxide production of the myenteric plexus in colitis detected by a new bioimaging system, J. Surg. Res, 117, 329, 10.1016/j.jss.2003.11.004 Willemze, 2019, Acetylcholine-producing T cells augment innate immune-driven colitis but are redundant in T cell-driven colitis, Am. J. Physiol. Gastrointest. Liver Physiol., 317, 10.1152/ajpgi.00067.2019 Winston, 2013, Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn's colitis and ulcerative colitis, Am. J. Physiol. Gastrointest. Liver Physiol., 305, G295, 10.1152/ajpgi.00052.2013 Axelsson, 1996, Dextran Sulfate Sodium (DSS) Induc. Exp. Colitis Immunodefic. mice: Eff. CD4(+) -Cell depleted, athymic NK-Cell depleted SCID mice. Inflamm. Res.: Off. J. Eur. Histamine Res. Soc. [Et. Al. ], 45, 181 Wirtz, 2007, Chemically induced mouse models of intestinal inflammation, Nat. Protoc., 2, 541, 10.1038/nprot.2007.41 da Silva, 2015, Differential effects of experimental ulcerative colitis on P2×7 receptor expression in enteric neurons, HISTOCHEMISTRY CELL Biol., 143, 171, 10.1007/s00418-014-1270-6 Hao, 2009, Development of enteric neuron diversity, J. Cell. Mol. Med., 13, 1193, 10.1111/j.1582-4934.2009.00813.x Timmermans, 2001, Outer submucous plexus: an intrinsic nerve network involved in both secretory and motility processes in the intestine of large mammals and humans, Anat. Rec., 262, 71, 10.1002/1097-0185(20010101)262:1<71::AID-AR1012>3.0.CO;2-A Goode, 2000, Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation, GUT, 47, 387, 10.1136/gut.47.3.387 Corrigan, 2016, Inflammation in acute CNS injury: a focus on the role of substance P, Br. J. PHARMACOLOGY, 173, 703, 10.1111/bph.13155 Mashaghi, 2016, Neuropeptide substance P and the immune response, Cell. Mol. Life Sci., 73, 4249, 10.1007/s00018-016-2293-z Reinshagen, 1997, Neuropeptides in inflammatory bowel disease: an update, Inflamm. Bowel Dis., 3, 303, 10.1097/00054725-199712000-00008 Stucchi, 2000, NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats, Am. J. Physiol.-Gastrointest. LIVER Physiol., 279, G1298, 10.1152/ajpgi.2000.279.6.G1298 Krause, 1987, Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A, Proc. Natl. Acad. Sci. USA, 84, 881, 10.1073/pnas.84.3.881 Rameshwar, 1997, Hematopoietic modulation by the tachykinins, Acta Haematol., 98, 59, 10.1159/000203593 Smits, 1994, Tachykinin receptors involved in the contractile effect of the natural tachykinins in the rat gastric fundus, J. Auton. Pharmacol., 14, 383, 10.1111/j.1474-8673.1994.tb00619.x Bennet, 2016, Global cytokine profiles and association with clinical characteristics in patients with irritable bowel syndrome, Am. J. Gastroenterol., 111, 1165, 10.1038/ajg.2016.223 Stucchi, 2000, NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats, Am. J. Physiol. Gastrointest. Liver Physiol., 279, G1298, 10.1152/ajpgi.2000.279.6.G1298 Di Sebastiano, 1999, SR140333, a substance P receptor antagonist, influences morphological and motor changes in rat experimental colitis, Dig. Dis. Sci., 44, 439, 10.1023/A:1026639509036 Sturiale, 1999, Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P, Proc. Natl. Acad. Sci. USA, 96, 11653, 10.1073/pnas.96.20.11653 Birder, 2003, Effect of nepadutant, a neurokinin 2 tachykinin receptor antagonist, on immediate-early gene expression after trinitrobenzenesulfonic acid-induced colitis in the, J. PHARMACOLOGY Exp. THERAPEUTICS, 304, 272, 10.1124/jpet.102.042077 Laird, 2000, Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene, NEUROSCIENCE, 98, 345, 10.1016/S0306-4522(00)00148-2 Bradesi, 2006, The role of neurokinin 1 receptors in the maintenance of visceral hyperalgesia induced by repeated stress in rats, GASTROENTEROLOGY, 130, 1729, 10.1053/j.gastro.2006.01.037 Waschek, 2013, VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair, Br. J. PHARMACOLOGY, 169, 512, 10.1111/bph.12181 Kochanowski, 2015, Assessment of plasma brain-derived neurotrophic factor (BDNF), activity-dependent neurotrophin protein (ADNP) and vasoactive intestinal peptide (VIP) concentrations in treatment-naive humans with multiple sclerosis, NEUROENDOCRINOLOGY Lett., 36, 148 Tomita, 2000, Peptidergic nerves in the colon of patients with ulcerative colitis, HEPATO-Gastroenterology, 47, 400 Schultebockholt, 1993, Gene-expression of vip in sigmoid colon from chronic ulcerative-colitis (cuc), Gastroenterology, 104 Boyer, 2007, Differential responses of VIPergic and nitrergic neurons in paediatric patients with Crohn's disease, Autonomic Neurosci.-BASIC Clin., 134, 106, 10.1016/j.autneu.2007.03.001 Gross, 2007, Role of neuropeptides in inflammatory bowel disease, Inflamm. Bowel Dis., 13, 918, 10.1002/ibd.20129 Song, 2021, The role of vasoactive intestinal peptide and mast cells in the regulatory effect of lactobacillus casei ATCC 393 on intestinal mucosal immune barrier, Front. Immunology, 12, 10.3389/fimmu.2021.723173 McDougall, 2005, The role of joint nerves and mast cells in the alteration of vasoactive intestinal peptide (VIP) sensitivity during inflammation progression in rats, Br. J. Pharmacology, 145, 104, 10.1038/sj.bjp.0706169 Seillet, 2020, The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity, Nat. Immunology, 21, 168, 10.1038/s41590-019-0567-y Li, 2016, Changes in enteric neurons of small intestine in a rat model of irritable bowel syndrome with diarrhea, J. Neurogastroenterol. Motil., 22, 310, 10.5056/jnm15082 Chandrasekharan, 2013, Emerging neuropeptide targets in inflammation: NPY and VIP, Am. J. Physiol. Gastrointest. Liver Physiol., 304, G949, 10.1152/ajpgi.00493.2012 Chandrasekharan, 2022, Intracolonic neuropeptide Y Y1 receptor inhibition attenuates intestinal inflammation in murine colitis and cytokine release in IBD biopsies, Inflamm. Bowel Dis., 28, 502, 10.1093/ibd/izab243 Zhang, 2008, Correlation of gut hormones with irritable bowel syndrome, Digestion, 78, 72, 10.1159/000165352 Morise, 1992, [Role of gut hormones in irritable bowel syndrome, Nihon Rinsho, 50, 2697 Chao, 2021, Research on correlation between psychological factors, mast cells, and PAR-2 signal pathway in irritable bowel syndrome, J. Inflamm. Res, 14, 1427, 10.2147/JIR.S300513 Hoover, 2017, Cholinergic modulation of the immune system presents new approaches for treating inflammation, Pharm. Ther., 179, 1, 10.1016/j.pharmthera.2017.05.002 Cox, 2020, Beyond neurotransmission: acetylcholine in immunity and inflammation, J. Intern Med, 287, 120, 10.1111/joim.13006 Ye, 2022, α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates DSS-induced intestinal colitis by improving intestinal mucosal barrier function, Mol. Med, 28, 10.1186/s10020-022-00485-6 Lei, 2022, Activation of α7nAChR preserves intestinal barrier integrity by enhancing the HO-1 / STAT3 signaling to inhibit NF-κB activation in mice, Biomed. Pharm., 149, 10.1016/j.biopha.2022.112733 Di Pinto, 2018, Comparative study of the expression of cholinergic system components in the CNS of experimental autoimmune encephalomyelitis mice: Acute vs remitting phase, Eur. J. Neurosci., 48, 2165, 10.1111/ejn.14125 Bodin, 2021, The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons, J. Biol. Chem., 297, 10.1016/j.jbc.2021.101300 Zhang, 2022, EphrinB2/ephB2 activation facilitates colonic synaptic potentiation and plasticity contributing to long-term visceral hypersensitivity in irritable bowel syndrome, Life Sci., 295, 10.1016/j.lfs.2022.120419 Yang, 2009, Synaptic plasticity: the new explanation of visceral hypersensitivity in rats with Trichinella spiralis infection?, Dig. Dis. Sci., 54, 937, 10.1007/s10620-008-0444-2 Bodin, 2021, The ephrin receptor EphB2 regulates the connectivity and activity of enteric neurons, J. Biol. Chem., 297, 10.1016/j.jbc.2021.101300 Ghoshal, 2011, Post-infectious irritable bowel syndrome: The past, the present and the future, J. Gastroenterol. Hepatol., 26, 94, 10.1111/j.1440-1746.2011.06643.x Xu, 2018, Electroacupuncture relieves visceral hypersensitivity by inactivating protease-activated receptor 2 in a rat model of postinfectious irritable bowel syndrome, Evid.-Based complementary alternative Med., 2018, 10.1155/2018/7048584 Teng, 2016, Expression and distribution of SP and its NK1 receptor in the brain-gut axis in neonatal maternally separated rat model with visceral hypersensitivity, Genet. Mol. Res., 15, 10.4238/gmr.15038999 Spiller, 2009, Overlap between irritable bowel syndrome and inflammatory bowel disease, Digestive Dis., 27, 48, 10.1159/000268121 Stead, 2006, Vagal influences over mast cells, Autonomic Neurosci.-BASIC Clin., 125, 53, 10.1016/j.autneu.2006.01.002 Traini, 2016, Changes of excitatory and inhibitory neurotransmitters in the colon of rats underwent to the wrap partial restraint stress, NEUROGASTROENTEROLOGY Motil., 28, 1172, 10.1111/nmo.12816 Verma-Gandhu, 2007, Visceral pain perception is determined by the duration of colitis and associated neuropeptide expression in the mouse, Gut, 56, 358, 10.1136/gut.2006.100016 Barreau, 2008, Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats, Gut, 57, 582, 10.1136/gut.2007.126680 Park, 2006, [The pathophysiology of irritable bowel syndrome: inflammation and motor disorder], Korean J. Gastroenterol., 47, 101 Ohman, 2010, Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions, Nat. Rev. Gastroenterol. Hepatol., 7, 163, 10.1038/nrgastro.2010.4 Peng, 2010, Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B, Am. J. Physiol. Ren. Physiol., 298, F109, 10.1152/ajprenal.00287.2009 Takasugi, 2017, Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2, Nat. Commun., 8, 15729, 10.1038/ncomms15728 Kang, 2018, Bifunctional role of ephrin A1-Eph system in stimulating cell proliferation and protecting cells from cell death through the attenuation of ER stress and inflammatory responses in bovine mammary epithelial cells, J. Cell. Physiol., 233, 2560, 10.1002/jcp.26131 Theofanous, 2020, Ephrin-B2 signaling in the spinal cord as a player in post-inflammatory and stress-induced visceral hypersensitivity, Neurogastroenterol. Motil.: Off. J. Eur. Gastrointest. Motil. Soc., 32, 10.1111/nmo.13782 Shin, 2014, Exocytosis and synaptic vesicle function, Compr. Physiol., 4, 149, 10.1002/cphy.c130021 Juan, 2014, J. Pineal Res., 56, 213, 10.1111/jpi.12114 Obrenovitch, 1997, Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic efficacy, Prog. Neurobiol., 51, 39, 10.1016/S0301-0082(96)00049-4 Reeds, 2000, Intestinal glutamate metabolism, J. Nutr., 130, 978S, 10.1093/jn/130.4.978S Blachier, 2009, Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines, Am. J. Clin. Nutr., 90, 814S, 10.3945/ajcn.2009.27462S Tsai, 2005, Function of GABAergic and glutamatergic neurons in the stomach, J. Biomed. Sci., 12, 255, 10.1007/s11373-005-1357-0 Traynelis, 2010, Glutamate receptor ion channels: structure, regulation, and function, Pharmacol. Rev., 62, 405, 10.1124/pr.109.002451 McRoberts, 2001, Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats, Gastroenterology, 120, 1737, 10.1053/gast.2001.24848 Takasu, 2002, Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors, Sci. (N. Y., N. Y. ), 295, 491, 10.1126/science.1065983 Liu, 2013, EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord, Pain, 154, 2823, 10.1016/j.pain.2013.08.017 Filpa, 2015, Interaction between NMDA glutamatergic and nitrergic enteric pathways during in vitro ischemia and reperfusion, Eur. J. Pharmacol., 750, 123, 10.1016/j.ejphar.2015.01.021 Zeng, 2018, A novel EphA2 inhibitor exerts beneficial effects in PI-IBS in Vivo and in Vitro Models via Nrf2 and NF-κB signaling pathways, Front. Pharmacol., 9, 272, 10.3389/fphar.2018.00272 Battaglia, 2003, EphB receptors and ephrin-B ligands regulate spinal sensory connectivity and modulate pain processing, Nat. Neurosci., 6, 339, 10.1038/nn1034 Wilkinson, 2001, Multiple roles of EPH receptors and ephrins in neural development, Nat. Rev. Neurosci., 2, 155, 10.1038/35058515 Zhao, 2010, Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain, Mol. Pain., 6, 77, 10.1186/1744-8069-6-77 Morales-Soto, 2019, Enteric glia: a new player in abdominal pain, Cell. Mol. Gastroenterol. Hepatol., 7, 433, 10.1016/j.jcmgh.2018.11.005 Mayer, 2001, Basic pathophysiologic mechanisms in irritable bowel syndrome, Dig. Dis. (Basel, Switz. ), 19, 212 Teruel, 2016, Diagnosis and management of functional symptoms in inflammatory bowel disease in remission, World J. Gastrointest. Pharmacol. Ther., 7, 78, 10.4292/wjgpt.v7.i1.78 Theofanous, 2020, Ephrin-B2 signaling in the spinal cord as a player in post-inflammatory and stress-induced visceral hypersensitivity, Neurogastroenterol. Motil., 32, 10.1111/nmo.13782 Song, 2008, EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats, Pain, 139, 168, 10.1016/j.pain.2008.03.019 Deng, 2017, Activation of ephrinB-EphB receptor signalling in rat spinal cord contributes to maintenance of diabetic neuropathic pain, Eur. J. Pain. (Lond., Engl. ), 21, 278, 10.1002/ejp.922 Hanamura, 2017, Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain, PLoS Biol., 15, 10.1371/journal.pbio.2002457 Nolt, 2011, EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner, J. Neurosci.: Off. J. Soc. Neurosci., 31, 5353, 10.1523/JNEUROSCI.0282-11.2011 Truitt, 2010, The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells, Cancer Res., 70, 1141, 10.1158/0008-5472.CAN-09-1710 King, 2014, Acute DSS colitis alters EphB6 receptor expression in neurons of the spinal dorsal horn, Neurosci. Lett., 559, 105, 10.1016/j.neulet.2013.11.041 Funk, 2013, Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis, Pharmacol. Res., 67, 42, 10.1016/j.phrs.2012.10.008 Perez White, 2014, Eph receptor and ephrin function in breast, gut, and skin epithelia, Cell Adhes. Migr., 8, 327, 10.4161/19336918.2014.970012 Rosenberg, 1997, Epithelial cell kinase-B61: an autocrine loop modulating intestinal epithelial migration and barrier function, Am. J. Physiol., 273, G824 Zhang, 2021, RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis, Autophagy, 17, 3030, 10.1080/15548627.2020.1851496 Kim, 2020, Inhibition of EphA2 by dasatinib suppresses radiation-induced intestinal injury, Int. J. Mol. Sci., 21, 10.3390/ijms21239096 Kaur, 2020, Potential role of EphrinA2 receptors in postconditioning induced cardioprotection in rats, Eur. J. Pharmacol., 883, 10.1016/j.ejphar.2020.173231 Vollmar, 2011, Intestinal ischemia/reperfusion: microcirculatory pathology and functional consequences, Lange 'S. Arch. Surg., 396, 13, 10.1007/s00423-010-0727-x Ivanov, 2006, Putative dual role of ephrin-Eph receptor interactions in inflammation, IUBMB Life, 58, 389, 10.1080/15216540600756004 Castelli, 2015, Δ(5)-Cholenoyl-amino acids as selective and orally available antagonists of the Eph-ephrin system., Eur. J. Med. Chem., 103, 312, 10.1016/j.ejmech.2015.08.048 Vivo, 2017, Protection by the Eph-Ephrin system against mesenteric ischemia-reperfusion injury, Shock, 48, 681, 10.1097/SHK.0000000000000890 Kirsch, 2010, p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis, Science, 327, 593, 10.1126/science.1166202 Dimitrievich, 1984, Radiosensitivity of vascular tissue. I. Differential radiosensitivity of capillaries: a quantitative in vivo study, Radiat. Res., 99, 511, 10.2307/3576327