Adenosine plays an important role in regulating intestinal motility and inflammatory processes. Previous studies in rodent models have demonstrated that adenosine metabolism and signalling are altered during chronic intestinal inflammatory diseases. However, the involvement of the adenosinergic system in the pathophysiology of gut dysmotility associated to a primary neurodysfunction is still unclear. Recently, we showed that the neurotropic Herpes simplex virus type-1 (HSV-1), orally inoculated to rodents, infects the rat enteric nervous system (ENS) and affects gut motor function without signs of systemic infection. In this study we examined whether changes in purinergic metabolism and signaling occur during permanent HSV-1 infection of rat ENS. Using isolated organ bath assays, we found that contraction mediated by adenosine engagement of A1 or A2A receptors was impaired at 1 and 6 weeks post-viral administration. Immunofluorescence studies revealed that viral infection of ENS led to a marked redistribution of adenosine receptors: A1 and A2B receptors were confined to the muscle layers whereas A2A and A3 receptors were expressed mainly in the myenteric plexus. Viral-induced ENS neurodysfunction influenced adenosine metabolism by increasing adenosine deaminase and CD73 levels in longitudinal muscle-myenteric plexus with no sign of frank inflammation. This study provides the first evidence for involvement of the adenosinergic system during HSV-1 infection of the ENS. As such, this may represent a valid therapeutic target for modulating gut contractility associated to a primary neurodysfunction.
References
[1]
Di Nardo G, Blandizzi C, Volta U, Colucci R, Stanghellini V, et al. (2008) Molecular, pathological and therapeutic features of human enteric neuropathies. Aliment Pharmacol Ther 28: 25–42.
[2]
De Giorgio R, Guerrini S, Barbara G, Cremon C, Stanghellini V, et al. (2004) New insights into human enteric neuropathies. Neurogastroenterol Motil 16: 143–147.
[3]
Gershon AA, Chen J, Gershon MD (2008) A model of lytic, latent, and reactivating varicella-zoster virus infections in isolated enteric neurons. J Infect Dis 197: S61–S65.
[4]
De Giorgio R, Guerrini S, Barbara G, Stanghellini V, De Ponti F, et al. (2004) Inflammatory neuropathies of the enteric nervous system. Gastroenterology 126: 1872–83.
[5]
De Giorgio R, Ricciardiello L, Naponelli V, Selgrad M, Piazzi G, et al. (2010) Chronic intestinal pseudo-obstruction related to viral infections. Transplant Proc 42: 9–14.
[6]
Roizman B, Knipe DM (2001) Herpes simplex viruses and their replication, In Howley PM, Knipe DM, editors. Virology, 4th ed. Lippincott-Raven, Philadelphia, Pa. 2399–2459.
[7]
Gesser RM, Valyi-Nagy T, Altschuler SM, Fraser NW (1994) Oral-esophageal inoculation of mice with herpes simplex virus type 1 causes latent infection of the vagal sensory ganglia (nodose ganglia). J Gen Virol 75: 2379–2386.
[8]
Gesser RM, Valyi-Nagy T, Fraser NW, Altschuler SM (1995) Oral inoculation of SCID mice with an attenuated HSV-1 strain causes persistent enteric nervous system infection and gastric ulcers without direct mucosal infection. Lab Invest 73: 880–889.
[9]
Gesser RM, Koo SC (1996) Oral inoculation with herpes simplex virus type 1 infects enteric neuron and mucosal nerve fibers within the gastrointestinal tract in mice. J Virol 70: 4097–4102.
[10]
Gesser RM, Koo SC (1997) Latent herpes simplex virus type 1 gene expression in ganglia innervating the human gastrointestinal tract. J Virol 71: 4103–4106.
[11]
Brun P, Giron MC, Zoppellaro C, Bin A, Porzionato A, et al. (2010) Herpes simplex virus type 1 infection of the rat enteric nervous system evokes small-bowel neuromuscular abnormalities. Gastroenterology 138: 1790–1801.
[12]
Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, et al. (2008) Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol Ther 120: 233–253.
[13]
Kolachala VL, Bajaj R, Chalasani M, Sitaraman SV (2008) Purinergic receptors in gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 294: G401–G410.
[14]
Giron MC, Bin A, Brun P, Etteri S, Bolego C, et al. (2008) Cyclic AMP in rat ileum: evidence for the presence of an extracellular cyclic AMP-adenosine pathway. Gastroenterology 134: 1116–1126.
[15]
Kan Y, Okabayashi T, Yokota S, Yamamoto S, Fujii N, et al. (2012) Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin A via the adenosine receptor A1 pathway. J Virol 86: 10338–10346.
[16]
Kas-Deelen AM, Bakker WW, Olinga P, Visser J, de Maar EF, et al. (2001) Cytomegalovirus infection increases the expression and activity of ecto-ATPase (CD39) and ecto-5′nucleotidase (CD73) on endothelial cells. FEBS Lett 491: 21–25.
[17]
De Man JG, Seerden TC, De Winter BY, Van Marck EA, Herman AG, et al. (2003) Alteration of the purinergic modulation of enteric neurotransmission in the mouse ileum during chronic intestinal inflammation. Br J Pharmacol 139: 172–184.
[18]
Aulí M, Nasser Y, Ho W, Burgue？o JF, Keenan CM, et al. (2008) Neuromuscular changes in a rat model of colitis. Auton Neurosci 141: 10–21.
[19]
Voltan S, Martines D, Elli M, Brun P, Longo S, et al. (2008) Lactobacillus crispatus M247-derived H2O2 acts as a signal transducing molecule activating peroxisome proliferator activated receptor-gamma in the intestinal mucosa. Gastroenterology 135: 1216–1227.
[20]
Bornstein JC (2008) Purinergic mechanisms in the control of gastrointestinal motility. Purinergic Signal 4: 197–212.
[21]
Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, et al. (2010) Control of enteric neuromuscular functions by purinergic A(3) receptors in normal rat distal colon and experimental bowel inflammation. Br J Pharmacol 161: 856–871.
[22]
Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, et al. (2011) Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis. Eur J Pharmacol 650: 639–649.
[23]
Nicholls J, Hourani SM (1997) Characterization of adenosine receptors on rat ileum, ileal longitudinal muscle and muscularis mucosae. Eur J Pharmacol 338: 143–150.
[24]
Zizzo MG, Bonomo A, Belluardo N, Mulè F, Serio R (2009) A1 receptors mediate adenosine inhibitory effects in mouse ileum via activation of potassium channels. Life Sci 84: 772–778.
[25]
Zizzo MG, Mastropaolo M, Lentini L, Mulè F, Serio R (2011) Adenosine negatively regulates duodenal motility in mice: role of A(1) and A(2A) receptors. Br J Pharmacol 164: 1580–1589.
[26]
Zizzo MG, Mulè F, Serio R (2006) Inhibitory responses to exogenous adenosine in murine proximal and distal colon. Br J Pharmacol 148: 956–963.
Murthy KS, McHenry L, Grider JR, Makhlouf GM (1995) Adenosine A1 and A2b receptors coupled to distinct interactive signaling pathways in intestinal muscle cells. J Pharmacol Exp Ther 274: 300–306.
[29]
Nicholls J, Brownhill VR, Hourani SMO (1996) Characterization of P1-purinoceptors on rat isolated duodenum longitudinal muscle and muscularis mucosae. Br J Pharmacol 117: 170–174.
[30]
Duarte-Araújo M, Nascimento C, Alexandrina Timóteo M, Magalh？es-Cardoso T, Correia-de-Sá P (2004) Dual effects of adenosine on acetylcholine release from myenteric motoneurons are mediated by junctional facilitatory A(2A) and extrajunctional inhibitory A(1) receptors. Br J Pharmacol 141: 925–934.
[31]
Coupar IM (1999) Characterization and tissue location of the neural adenosine receptor in the rat ileum. Br J Pharmacol 126: 1269–1275.
[32]
Christofi FL, Zhang H, Yu JG, Guzman J, Xue J, et al. (2001) Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J Comp Neurol 439: 46–64.
[33]
Kadowaki M, Takeda M, Tokita K, Hanaoka K, Tomoi M (2000) Molecular identification and pharmacological characterization of adenosine receptors in the guinea-pig colon. Br J Pharmacol 129: 871–876.
[34]
Vieira C, Ferreirinha F, Silva I, Duarte-Araújo M, Correia-de-Sá P (2011) Localization and function of adenosine receptor subtypes at the longitudinal muscle–myenteric plexus of the rat ileum. Neurochem Int 59: 1043–1055.
[35]
Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, et al. (2010) The blockade of adenosine deaminase ameliorates chronic experimental colitis through the recruitment of adenosine A2A and A3 receptors. J Pharmacol Exp Ther 335: 434–42.
[36]
Kolachala VL, Vijay-Kumar M, Dalmasso G, Yang D, Linden J, et al. (2008) A2B adenosine receptor gene deletion attenuates murine colitis. Gastroenterology 135: 861–870.
[37]
Colgan SP, Fennimore B, Ehrentraut SF (2013) Adenosine and gastrointestinal inflammation. J Mol Med (Berl) 91: 157–164.
[38]
Nitahara K, Kittel A, Liang SD, Vizi ES (1995) A1-receptor-mediated effect of adenosine on the release of acetylcholine from the myenteric plexus: role and localization of ecto-ATPase and 5′-nucleotidase. Neuroscience 67: 159–168.
[39]
Antonioli L, Colucci R, La Motta C, Tuccori M, Awwad O, et al. (2012) Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 13: 842–862.
[40]
Colgan SP, Eltzschig HK, Eckle T, Thompson LF (2006) Physiological roles for ecto-5′-nucleotidase (CD73). Purinergic Signal 2: 351–360.
[41]
Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, et al. (2006) Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 108: 1602–1610.
[42]
Correia-de-Sá P, Ad？es S, Timóteo MA, Vieira C, Magalh？es-Cardoso T, et al. (2006) Fine-tuning modulation of myenteric motoneurons by endogenous adenosine: on the role of secreted adenosine deaminase. Auton Neurosci 126–127: 211–224.
[43]
Schwiebert EM, Fitz JG (2008) Purinergic signaling microenvironments: an introduction. Purinergic Signal 4: 89–92.
[44]
Volonté C, D’Ambrosi N, Amadio S (2008) Protein cooperation: from neurons to networks. Prog Neurobiol 86: 61–71.
