Skip to main content

Advertisement

SpringerLink
Log in

Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This “cholinergic anti-inflammatory pathway” modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Haverslag R, Pasterkamp G, Hoefer IE (2008) Targeting adhesion molecules in cardiovascular disorders. Cardiovasc Hematol Disord Drug Targets 8:252–260

    Article  CAS  PubMed  Google Scholar 

  2. Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125:S3–S23

    Article  PubMed  Google Scholar 

  3. Loiarro M, Ruggiero V, Sette C (2010) Targeting TLR/IL-1R signalling in human diseases. Mediators Inflamm 2010:674363

    Article  PubMed  CAS  Google Scholar 

  4. Opal SM (2010) Endotoxins and other sepsis triggers. Contrib Nephrol 167:14–24

    Article  CAS  PubMed  Google Scholar 

  5. Commins SP, Borish L, Steinke JW (2010) Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol 125:S53–S72

    Article  PubMed  Google Scholar 

  6. Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78:539–552

    Article  CAS  PubMed  Google Scholar 

  7. Duvnjak L, Duvnjak M (2009) The metabolic syndrome—an ongoing story. J Physiol Pharmacol 60(Suppl 7):19–24

    PubMed  Google Scholar 

  8. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246

    Article  CAS  PubMed  Google Scholar 

  9. Tzanavari T, Giannogonas P, Karalis KP (2010) TNF-alpha and obesity. Curr Dir Autoimmun 11:145–156

    Article  CAS  PubMed  Google Scholar 

  10. Jiao P, Chen Q, Shah S, Du J, Tao B, Tzameli I, Yan W, Xu H (2009) Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways. Diabetes 58:104–115

    Article  CAS  PubMed  Google Scholar 

  11. Rabe K, Lehrke M, Parhofer KG, Broedl UC (2008) Adipokines and insulin resistance. Mol Med 14:741–751

    Article  CAS  PubMed  Google Scholar 

  12. Filkova M, Haluzik M, Gay S, Senolt L (2009) The role of resistin as a regulator of inflammation: implications for various human pathologies. Clin Immunol 133:157–170

    Article  CAS  PubMed  Google Scholar 

  13. Folco EJ, Rocha VZ, Lopez-Ilasaca M, Libby P (2009) Adiponectin inhibits pro-inflammatory signaling in human macrophages independent of interleukin-10. J Biol Chem 284:25569–25575

    Article  CAS  PubMed  Google Scholar 

  14. Devaraj S, Singh U, Jialal I (2009) Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol 20:182–189

    Article  CAS  PubMed  Google Scholar 

  15. Galasko D, Montine TJ (2010) Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomark Med 4:27–36

    Article  CAS  PubMed  Google Scholar 

  16. Mandrekar-Colucci S, Landreth GE (2010) Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9:156–167

    CAS  PubMed  Google Scholar 

  17. Tan ZS, Seshadri S (2010) Inflammation in the Alzheimer’s disease cascade: culprit or innocent bystander? Alzheimers Res Ther 2:6

    Article  PubMed  Google Scholar 

  18. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39:1–16

    Article  CAS  PubMed  Google Scholar 

  19. Brennan FM, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545

    Article  CAS  PubMed  Google Scholar 

  20. Jazayeri JA, Carroll GJ, Vernallis AB (2010) Interleukin-6 subfamily cytokines and rheumatoid arthritis: role of antagonists. Int Immunopharmacol 10:1–8

    Article  CAS  PubMed  Google Scholar 

  21. Toussirot E, Wendling D (2007) The use of TNF-alpha blocking agents in rheumatoid arthritis: an update. Expert Opin Pharmacother 8:2089–2107

    Article  CAS  PubMed  Google Scholar 

  22. Lubberts E (2010) Th17 cytokines and arthritis. Semin Immunopathol 32:43–53

    Article  CAS  PubMed  Google Scholar 

  23. Lee S, Ballow M (2010) Monoclonal antibodies and fusion proteins and their complications: targeting B cells in autoimmune diseases. J Allergy Clin Immunol 125:814–820

    Article  CAS  PubMed  Google Scholar 

  24. Nigrovic PA, Lee DM (2007) Synovial mast cells: role in acute and chronic arthritis. Immunol Rev 217:19–37

    Article  CAS  PubMed  Google Scholar 

  25. Nigrovic PA, Binstadt BA, Monach PA, Johnsen A, Gurish M, Iwakura Y, Benoist C, Mathis D, Lee DM (2007) Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc Natl Acad Sci USA 104:2325–2330

    Article  CAS  PubMed  Google Scholar 

  26. Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233–255

    Article  CAS  PubMed  Google Scholar 

  27. Uysal H, Nandakumar KS, Kessel C, Haag S, Carlsen S, Burkhardt H, Holmdahl R (2010) Antibodies to citrullinated proteins: molecular interactions and arthritogenicity. Immunol Rev 233:9–33

    Article  CAS  PubMed  Google Scholar 

  28. Dua B, Watson RM, Gauvreau GM, O’Byrne PM (2010) Myeloid and plasmacytoid dendritic cells in induced sputum after allergen inhalation in subjects with asthma. J Allergy Clin Immunol 126:133–139

    Article  CAS  PubMed  Google Scholar 

  29. Holt PG, Strickland DH (2010) Interactions between innate and adaptive immunity in asthma pathogenesis: new perspectives from studies on acute exacerbations. J Allergy Clin Immunol 125:963–972

    Article  CAS  PubMed  Google Scholar 

  30. Finkelman FD, Hogan SP, Hershey GK, Rothenberg ME, Wills-Karp M (2010) Importance of cytokines in murine allergic airway disease and human asthma. J Immunol 184:1663–1674

    Article  CAS  PubMed  Google Scholar 

  31. Barnes PJ (2007) New molecular targets for the treatment of neutrophilic diseases. J Allergy Clin Immunol 119:1055–1062

    Article  CAS  PubMed  Google Scholar 

  32. Tavakkol AJ, Farid HR, Hosseini FS, Heydarian F, Boskabady MH, Khoshnavaz R, Razavi A, Ghayoor KE, Ghasemi G (2007) Association of the expression of IL-4 and IL-13 genes, IL-4 and IgE serum levels with allergic asthma. Iran J Allergy Asthma Immunol 6:67–72

    Google Scholar 

  33. Busse WW, Ring J, Huss-Marp J, Kahn JE (2010) A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J Allergy Clin Immunol 125:803–813

    Article  CAS  PubMed  Google Scholar 

  34. Ribeiro F, Alves AJ, Teixeira M, Ribeiro V, Duarte JA, Oliveira J (2009) Endothelial function and atherosclerosis: circulatory markers with clinical usefulness. Rev Port Cardiol 28:1121–1151

    PubMed  Google Scholar 

  35. Lubos E, Handy DE, Loscalzo J (2008) Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci 13:5323–5344

    Article  CAS  PubMed  Google Scholar 

  36. Rodriguez G, Mago N, Rosa F (2009) Role of inflammation in atherogenesis. Invest Clin 50:109–129

    PubMed  Google Scholar 

  37. Puddu P, Puddu GM, Cravero E, De Pascalis S, Muscari A (2009) The emerging role of cardiovascular risk factor-induced mitochondrial dysfunction in atherogenesis. J Biomed Sci 16:112

    Article  PubMed  CAS  Google Scholar 

  38. McNeill E, Channon KM, Greaves DR (2010) Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications. Clin Sci (Lond) 118:641–655

    Article  CAS  Google Scholar 

  39. Woollard KJ, Geissmann F (2010) Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7:77–86

    Article  PubMed  Google Scholar 

  40. Sgambato A, Cittadini A (2010) Inflammation and cancer: a multifaceted link. Eur Rev Med Pharmacol Sci 14:263–268

    CAS  PubMed  Google Scholar 

  41. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  CAS  PubMed  Google Scholar 

  42. Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373

    Article  CAS  PubMed  Google Scholar 

  43. Wang CS, Sun CF (2009) C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung Med J 32:471–482

    PubMed  Google Scholar 

  44. Erdman SE, Rao VP, Olipitz W, Taylor CL, Jackson EA, Levkovich T, Lee CW, Horwitz BH, Fox JG, Ge Z, Poutahidis T (2010) Unifying roles for regulatory T cells and inflammation in cancer. Int J Cancer 126:1651–1665

    CAS  PubMed  Google Scholar 

  45. Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C (2007) Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer 121:2381–2386

    Article  CAS  PubMed  Google Scholar 

  46. Kreindler JL (2010) Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. Pharmacol Ther 125:219–229

    Article  CAS  PubMed  Google Scholar 

  47. Koller B, Kappler M, Latzin P, Gaggar A, Schreiner M, Takyar S, Kormann M, Kabesch M, Roos D, Griese M, Hartl D (2008) TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. J Immunol 181:2753–2763

    CAS  PubMed  Google Scholar 

  48. Matricon J (2010) Immunopathogenesis of inflammatory bowel disease. Med Sci (Paris) 26:405–410

    Google Scholar 

  49. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK (2008) Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14:4280–4288

    Article  CAS  PubMed  Google Scholar 

  50. Wei J, Feng J (2010) Signaling pathways associated with inflammatory bowel disease. Recent Pat Inflamm Allergy Drug Discov 4:105–117

    Article  CAS  PubMed  Google Scholar 

  51. Polinska B, Matowicka-Karna J, Kemona H (2009) The cytokines in inflammatory bowel disease. Postepy Hig Med Dosw (Online) 63:389–394

    Google Scholar 

  52. Tonel G, Conrad C (2009) Interplay between keratinocytes and immune cells—recent insights into psoriasis pathogenesis. Int J Biochem Cell Biol 41:963–968

    Article  CAS  PubMed  Google Scholar 

  53. Spah F (2008) Inflammation in atherosclerosis and psoriasis: common pathogenic mechanisms and the potential for an integrated treatment approach. Br J Dermatol 159(Suppl 2):10–17

    Article  PubMed  CAS  Google Scholar 

  54. Mazza J, Rossi A, Weinberg JM (2010) Innovative uses of tumor necrosis factor alpha inhibitors. Dermatol Clin 28:559–575

    Article  CAS  PubMed  Google Scholar 

  55. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A (2007) Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep 9:461–467

    Article  CAS  PubMed  Google Scholar 

  56. Ishii M, Kurachi Y (2006) Muscarinic acetylcholine receptors. Curr Pharm Des 12:3573–3581

    Article  CAS  PubMed  Google Scholar 

  57. Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, Manfredi I, Moretti M, Pedrazzi P, Pucci L, Zoli M (2009) Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem Pharmacol 78:703–711

    Article  CAS  PubMed  Google Scholar 

  58. Sharma G, Vijayaraghavan S (2008) Nicotinic receptors containing the alpha7 subunit: a model for rational drug design. Curr Med Chem 15:2921–2932

    Article  CAS  PubMed  Google Scholar 

  59. Shen JX, Yakel JL (2009) Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin 30:673–680

    Article  CAS  PubMed  Google Scholar 

  60. Leiser SC, Bowlby MR, Comery TA, Dunlop J (2009) A cog in cognition: how the alpha 7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol Ther 122:302–311

    Article  CAS  PubMed  Google Scholar 

  61. de Jonge WJ, Ulloa L (2007) The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 151:915–929

    Article  PubMed  CAS  Google Scholar 

  62. Kawashima K, Fujii T (2008) Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci 106:167–173

    Article  CAS  PubMed  Google Scholar 

  63. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117:289–296

    Article  CAS  PubMed  Google Scholar 

  64. Wang DW, Zhou RB, Yao YM (2009) Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases. Chin J Traumatol 12:355–364

    CAS  PubMed  Google Scholar 

  65. van Westerloo DJ (2010) The vagal immune reflex: a blessing from above. Wien Med Wochenschr 160:112–117

    Article  PubMed  Google Scholar 

  66. Ulloa L (2005) The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov 4:673–684

    Article  CAS  PubMed  Google Scholar 

  67. Dowling O, Rochelson B, Way K, Al-Abed Y, Metz CN (2007) Nicotine inhibits cytokine production by placenta cells via NFkappaB: potential role in pregnancy-induced hypertension. Mol Med 13:576–583

    Article  CAS  PubMed  Google Scholar 

  68. Saeed RW, Varma S, Peng-Nemeroff T, Sherry B, Balakhaneh D, Huston J, Tracey KJ, Al-Abed Y, Metz CN (2005) Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med 201:1113–1123

    Article  CAS  PubMed  Google Scholar 

  69. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343

    Article  CAS  PubMed  Google Scholar 

  70. Moon JH, Kim SY, Lee HG, Kim SU, Lee YB (2008) Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar beta amyloid peptide (1-42)-stimulated microglia. Exp Mol Med 40:11–18

    Article  CAS  PubMed  Google Scholar 

  71. Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Yang LH, Hudson L, Lin X, Patel N, Johnson SM, Chavan S, Goldstein RS, Czura CJ, Miller EJ, Al-Abed Y, Tracey KJ, Pavlov VA (2008) Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med 14:567–574

    Article  CAS  PubMed  Google Scholar 

  72. Rosas-Ballina M, Tracey KJ (2009) Cholinergic control of inflammation. J Intern Med 265:663–679

    Article  CAS  PubMed  Google Scholar 

  73. van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L, Tracey KJ, van der Poll T (2006) The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 130:1822–1830

    Article  PubMed  CAS  Google Scholar 

  74. van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, van der Poll T (2005) The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J Infect Dis 191:2138–2148

    Article  PubMed  Google Scholar 

  75. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6:844–851

    Article  PubMed  CAS  Google Scholar 

  76. Gahring LC, Rogers SW (2005) Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells. AAPS J 7:E885–E894

    Article  CAS  Google Scholar 

  77. Davies BD, Hoss W, Lin JP, Lionetti F (1982) Evidence for a noncholinergic nicotine receptor on human phagocytic leukocytes. Mol Cell Biochem 44:23–31

    Article  CAS  PubMed  Google Scholar 

  78. Benhammou K, Lee M, Strook M, Sullivan B, Logel J, Raschen K, Gotti C, Leonard S (2000) [(3)H]Nicotine binding in peripheral blood cells of smokers is correlated with the number of cigarettes smoked per day. Neuropharmacology 39:2818–2829

    Article  CAS  PubMed  Google Scholar 

  79. De Rosa MJ, Dionisio L, Agriello E, Bouzat C, Esandi MC (2009) Alpha 7 nicotinic acetylcholine receptor modulates lymphocyte activation. Life Sci 85:444–449

    Article  PubMed  CAS  Google Scholar 

  80. Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–396

    Article  CAS  PubMed  Google Scholar 

  81. Chernyavsky AI, Arredondo J, Skok M, Grando SA (2010) Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors. Int Immunopharmacol 10:308–315

    Article  CAS  PubMed  Google Scholar 

  82. Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T (2009) Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J Immunol 183:6681–6688

    Article  CAS  PubMed  Google Scholar 

  83. Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdes-Ferrer SI, Patel NB, Chavan S, Al-Abed Y, Yang H, Tracey KJ (2009) The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med 15:195–202

    Article  CAS  PubMed  Google Scholar 

  84. Rehani K, Scott DA, Renaud D, Hamza H, Williams LR, Wang H, Martin M (2008) Cotinine-induced convergence of the cholinergic and PI3 kinase-dependent anti-inflammatory pathways in innate immune cells. Biochim Biophys Acta 1783:375–382

    Article  CAS  PubMed  Google Scholar 

  85. Tilg H, Moschen AR (2008) Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14:222–231

    Article  CAS  PubMed  Google Scholar 

  86. Zeyda M, Stulnig TM (2007) Adipose tissue macrophages. Immunol Lett 112:61–67

    Article  CAS  PubMed  Google Scholar 

  87. Maasen JA (2008) Mitochondria, body fat and type 2 diabetes: what is the connection? Minerva Med 99:241–251

    CAS  PubMed  Google Scholar 

  88. Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455

    Article  CAS  PubMed  Google Scholar 

  89. Liu RH, Mizuta M, Matsukura S (2004) The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J Pharmacol Exp Ther 310:52–58

    Article  CAS  PubMed  Google Scholar 

  90. Carnevale D, De Simone R, Minghetti L (2007) Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targets 6:388–397

    Article  CAS  PubMed  Google Scholar 

  91. Nizri E, Irony-Tur-Sinai M, Faranesh N, Lavon I, Lavi E, Weinstock M, Brenner T (2008) Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine. J Neuroimmunol 203:12–22

    Article  CAS  PubMed  Google Scholar 

  92. Guseva MV, Hopkins DM, Scheff SW, Pauly JR (2008) Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury. J Neurotrauma 25:975–983

    Article  PubMed  Google Scholar 

  93. Park HJ, Lee PH, Ahn YW, Choi YJ, Lee G, Lee DY, Chung ES, Jin BK (2007) Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci 26:79–89

    Article  PubMed  Google Scholar 

  94. Suzuki T, Hide I, Matsubara A, Hama C, Harada K, Miyano K, Andra M, Matsubayashi H, Sakai N, Kohsaka S, Inoue K, Nakata Y (2006) Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role. J Neurosci Res 83:1461–1470

    Article  CAS  PubMed  Google Scholar 

  95. van Maanen MA, Stoof SP, van der Zanden EP, de Jonge WJ, Janssen RA, Fischer DF, Vandeghinste N, Brys R, Vervoordeldonk MJ, Tak PP (2009) The alpha7 nicotinic acetylcholine receptor on fibroblast-like synoviocytes and in synovial tissue from rheumatoid arthritis patients: a possible role for a key neurotransmitter in synovial inflammation. Arthritis Rheum 60:1272–1281

    Article  PubMed  Google Scholar 

  96. Waldburger JM, Boyle DL, Pavlov VA, Tracey KJ, Firestein GS (2008) Acetylcholine regulation of synoviocyte cytokine expression by the alpha7 nicotinic receptor. Arthritis Rheum 58:3439–3449

    Article  CAS  PubMed  Google Scholar 

  97. Wang Y, Pereira EF, Maus AD, Ostlie NS, Navaneetham D, Lei S, Albuquerque EX, Conti-Fine BM (2001) Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors. Mol Pharmacol 60:1201–1209

    CAS  PubMed  Google Scholar 

  98. Blanchet MR, Langlois A, Israel-Assayag E, Beaulieu MJ, Ferland C, Laviolette M, Cormier Y (2007) Modulation of eosinophil activation in vitro by a nicotinic receptor agonist. J Leukoc Biol 81:1245–1251

    Article  CAS  PubMed  Google Scholar 

  99. Maouche K, Polette M, Jolly T, Medjber K, Cloez-Tayarani I, Changeux JP, Burlet H, Terryn C, Coraux C, Zahm JM, Birembaut P, Tournier JM (2009) Alpha7 nicotinic acetylcholine receptor regulates airway epithelium differentiation by controlling basal cell proliferation. Am J Pathol 175:1868–1882

    Article  CAS  PubMed  Google Scholar 

  100. Su X, Matthay MA, Malik AB (2010) Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury. J Immunol 184:401–410

    Article  CAS  PubMed  Google Scholar 

  101. Giebelen IA, van Westerloo DJ, Larosa GJ, de Vos AF, van der Poll T (2007) Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung. Shock 28:700–703

    CAS  PubMed  Google Scholar 

  102. Xu B, Makris A, Thornton C, Hennessy A (2005) Glucocorticoids inhibit placental cytokines from cultured normal and preeclamptic placental explants. Placenta 26:654–660

    Article  CAS  PubMed  Google Scholar 

  103. Kwon JY, Kim YH, Kim SH, Kang MH, Maeng YS, Lee KY, Park YW (2007) Difference in the expression of alpha 7 nicotinic receptors in the placenta in normal versus severe preeclampsia pregnancies. Eur J Obstet Gynecol Reprod Biol 132:35–39

    Article  CAS  PubMed  Google Scholar 

  104. Lips KS, Bruggmann D, Pfeil U, Vollerthun R, Grando SA, Kummer W (2005) Nicotinic acetylcholine receptors in rat and human placenta. Placenta 26:735–746

    Article  CAS  PubMed  Google Scholar 

  105. Kurzen H, Wessler I, Kirkpatrick CJ, Kawashima K, Grando SA (2007) The non-neuronal cholinergic system of human skin. Horm Metab Res 39:125–135

    Article  CAS  PubMed  Google Scholar 

  106. Moriwaki Y, Yoshikawa K, Fukuda H, Fujii YX, Misawa H, Kawashima K (2007) Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands. Life Sci 80:2365–2368

    Article  CAS  PubMed  Google Scholar 

  107. Favre B, Plantard L, Aeschbach L, Brakch N, Christen-Zaech S, de Viragh PA, Sergeant A, Huber M, Hohl D (2007) SLURP1 is a late marker of epidermal differentiation and is absent in Mal de Meleda. J Invest Dermatol 127:301–308

    Article  CAS  PubMed  Google Scholar 

  108. Chimienti F, Hogg RC, Plantard L, Lehmann C, Brakch N, Fischer J, Huber M, Bertrand D, Hohl D (2003) Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum Mol Genet 12:3017–3024

    Article  CAS  PubMed  Google Scholar 

  109. Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J (2003) Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 11:525–531

    Article  CAS  PubMed  Google Scholar 

  110. Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7

    Article  CAS  PubMed  Google Scholar 

  111. Marrero MB, Lucas R, Salet C, Hauser TA, Mazurov A, Lippiello PM, Bencherif M (2010) An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J Pharmacol Exp Ther 332:173–180

    Article  CAS  PubMed  Google Scholar 

  112. Gwilt CR, Donnelly LE, Rogers DF (2007) The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation? Pharmacol Ther 115:208–222

    Article  CAS  PubMed  Google Scholar 

  113. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, Jorgensen T (2001) Smoking and the development of allergic sensitization to aeroallergens in adults: a prospective population-based study. The Copenhagen Allergy Study. Allergy 56:328–332

    Article  CAS  PubMed  Google Scholar 

  114. Chen LY, Liu ZG, Li YH, Feng YZ, Wang JR (2008) Expression of neuronal acetylcholine receptor alpha 7 (nAChRalpha7) in peripheral blood CD(4)(+) T lymphocytes from asthmatic children. Zhonghua Jie He He Hu Xi Za Zhi 31:803–805

    PubMed  Google Scholar 

  115. Mishra NC, Rir-Sima-Ah J, Boyd RT, Singh SP, Gundavarapu S, Langley RJ, Razani-Boroujerdi S, Sopori ML (2010) Nicotine inhibits fcφ RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha7/alpha9/alpha10-nicotinic receptors. J Immunol 185:588–596

    Article  CAS  PubMed  Google Scholar 

  116. Greene CM, Ramsay H, Wells RJ, O’Neill SJ, McElvaney NG (2010) Inhibition of Toll-like receptor 2-mediated interleukin-8 production in cystic fibrosis airway epithelial cells via the alpha7-nicotinic acetylcholine receptor. Mediators Inflamm 2010:423241

    Article  PubMed  CAS  Google Scholar 

  117. Dorion G, Israel-Assayag E, Beaulieu MJ, Cormier Y (2005) Effect of 1, 1-dimethylphenyl 1,4-piperazinium on mouse tracheal smooth muscle responsiveness. Am J Physiol Lung Cell Mol Physiol 288:L1139–L1145

    Article  CAS  PubMed  Google Scholar 

  118. Zhang P, Han D, Tang T, Zhang X, Dai K (2008) Inhibition of the development of collagen-induced arthritis in Wistar rats through vagus nerve suspension: a 3-month observation. Inflamm Res 57:322–328

    Article  CAS  PubMed  Google Scholar 

  119. van Maanen MA, Lebre MC, van der Poll T, Larosa GJ, Elbaum D, Vervoordeldonk MJ, Tak PP (2009) Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum 60:114–122

    Article  PubMed  CAS  Google Scholar 

  120. van Maanen MA, Stoof SP, Larosa GJ, Vervoordeldonk MJ, Tak PP (2010) Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor alpha7 subunit gene knockout mice. Ann Rheum Dis 69:1717–1723

    Article  PubMed  Google Scholar 

  121. Chung YC, Ko HW, Bok E, Park ES, Huh SH, Nam JH, Jin BK (2010) The role of neuroinflammation on the pathogenesis of Parkinson’s disease. BMB Rep 43:225–232

    CAS  PubMed  Google Scholar 

  122. Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 11:999–1016

    Article  CAS  PubMed  Google Scholar 

  123. Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T (2005) Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 57:168–175

    Article  CAS  PubMed  Google Scholar 

  124. Ajonuma LC, Chan PK, Ng EH, Fok KL, Wong CH, Tsang LL, Tang XX, Ho LS, Lau MC, Chung CM, He Q, Huang HY, Yang DZ, Rowlands DK, Chung YW, Chan HC (2008) Involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of hydrosalpinx induced by Chlamydia trachomatis infection. J Obstet Gynaecol Res 34:923–930

    CAS  PubMed  Google Scholar 

  125. Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13:1925–1928

    Article  CAS  PubMed  Google Scholar 

  126. Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R (2008) Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson’s disease. Acta Neuropathol 116:47–55

    Article  CAS  PubMed  Google Scholar 

  127. Quik M, O’Leary K, Tanner CM (2008) Nicotine and Parkinson’s disease: implications for therapy. Mov Disord 23:1641–1652

    Article  PubMed  Google Scholar 

  128. Westman M, Engstrom M, Catrina AI, Lampa J (2009) Cell specific synovial expression of nicotinic alpha 7 acetylcholine receptor in rheumatoid arthritis and psoriatic arthritis. Scand J Immunol 70:136–140

    Article  CAS  PubMed  Google Scholar 

  129. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462

    Article  CAS  PubMed  Google Scholar 

  130. Wang H, Ward MF, Sama AE (2009) Novel HMGB1-inhibiting therapeutic agents for experimental sepsis. Shock 32:348–357

    Article  CAS  PubMed  Google Scholar 

  131. Ulloa L, Tracey KJ (2005) The “cytokine profile”: a code for sepsis. Trends Mol Med 11:56–63

    Article  CAS  PubMed  Google Scholar 

  132. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al-Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221

    Article  CAS  PubMed  Google Scholar 

  133. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, Tracey KJ, Ulloa L (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 203:1623–1628

    Article  CAS  PubMed  Google Scholar 

  134. Wittebole X, Hahm S, Coyle SM, Kumar A, Calvano SE, Lowry SF (2007) Nicotine exposure alters in vivo human responses to endotoxin. Clin Exp Immunol 147:28–34

    CAS  PubMed  Google Scholar 

  135. Clodi M, Vila G, Geyeregger R, Riedl M, Stulnig TM, Struck J, Luger TA, Luger A (2008) Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men. Am J Physiol Endocrinol Metab 295:E686–E691

    Article  CAS  PubMed  Google Scholar 

  136. Wu R, Dong W, Cui X, Zhou M, Simms HH, Ravikumar TS, Wang P (2007) Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Ann Surg 245:480–486

    Article  PubMed  Google Scholar 

  137. Hofer S, Eisenbach C, Lukic IK, Schneider L, Bode K, Brueckmann M, Mautner S, Wente MN, Encke J, Werner J, Dalpke AH, Stremmel W, Nawroth PP, Martin E, Krammer PH, Bierhaus A, Weigand MA (2008) Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit Care Med 36:404–408

    Article  CAS  PubMed  Google Scholar 

  138. Wolf JM, Lashner BA (2002) Inflammatory bowel disease: sorting out the treatment options. Cleve Clin J Med 69:621–631

    Article  PubMed  Google Scholar 

  139. Scott DA, Martin M (2006) Exploitation of the nicotinic anti-inflammatory pathway for the treatment of epithelial inflammatory diseases. World J Gastroenterol 12:7451–7459

    CAS  PubMed  Google Scholar 

  140. McGilligan VE, Wallace JM, Heavey PM, Ridley DL, Rowland IR (2007) Hypothesis about mechanisms through which nicotine might exert its effect on the interdependence of inflammation and gut barrier function in ulcerative colitis. Inflamm Bowel Dis 13:108–115

    Article  PubMed  Google Scholar 

  141. Aldhous MC, Prescott RJ, Roberts S, Samuel K, Waterfall M, Satsangi J (2008) Does nicotine influence cytokine profile and subsequent cell cycling/apoptotic responses in inflammatory bowel disease? Inflamm Bowel Dis 14:1469–1482

    Article  PubMed  Google Scholar 

  142. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM (2006) The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131:1122–1130

    Article  PubMed  Google Scholar 

  143. Ghia JE, Blennerhassett P, Collins SM (2007) Vagus nerve integrity and experimental colitis. Am J Physiol Gastrointest Liver Physiol 293:G560–G567

    Article  CAS  PubMed  Google Scholar 

  144. Miceli PC, Jacobson K (2003) Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats. Auton Neurosci 105:16–24

    Article  CAS  PubMed  Google Scholar 

  145. Bai A, Guo Y, Lu N (2007) The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 66:538–545

    Article  CAS  PubMed  Google Scholar 

  146. Ghia JE, Blennerhassett P, Collins SM (2008) Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J Clin Invest 118:2209–2218

    CAS  PubMed  Google Scholar 

  147. Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D (2005) Increased severity of experimental colitis in alpha 5 nicotinic acetylcholine receptor subunit-deficient mice. Neuroreport 16:1123–1127

    Article  CAS  PubMed  Google Scholar 

  148. Shaw S, Bencherif M, Marrero MB (2002) Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1–42) amyloid. J Biol Chem 277:44920–44924

    Article  CAS  PubMed  Google Scholar 

  149. Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, Kamochi H, Suzuki N (2006) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 146:116–123

    Article  CAS  PubMed  Google Scholar 

  150. Spoettl T, Paetzel C, Herfarth H, Bencherif M, Schoelmerich J, Greinwald R, Gatto GJ, Rogler G (2007) (E)-metanicotine hemigalactarate (TC-2403–12) inhibits IL-8 production in cells of the inflamed mucosa. Int J Colorectal Dis 22:303–312

    Article  PubMed  Google Scholar 

  151. Gahring LC, Days EL, Kaasch T, de Gonzalez MM, Owen L, Persiyanov K, Rogers SW (2005) Pro-inflammatory cytokines modify neuronal nicotinic acetylcholine receptor assembly. J Neuroimmunol 166:88–101

    Article  CAS  PubMed  Google Scholar 

  152. Skok MV, Grailhe R, Agenes F, Changeux JP (2007) The role of nicotinic receptors in B-lymphocyte development and activation. Life Sci 80:2334–2336

    Article  CAS  PubMed  Google Scholar 

  153. Oloris SC, Frazer-Abel AA, Jubala CM, Fosmire SP, Helm KM, Robinson SR, Korpela DM, Duckett MM, Baksh S, Modiano JF (2010) Nicotine-mediated signals modulate cell death and survival of T lymphocytes. Toxicol Appl Pharmacol 242:299–309

    Article  CAS  PubMed  Google Scholar 

  154. Nakao S, Ogata Y, Sugiya H (2009) Nicotine stimulates the expression of cyclooxygenase-2 mRNA via NFkappaB activation in human gingival fibroblasts. Arch Oral Biol 54:251–257

    Article  CAS  PubMed  Google Scholar 

  155. Xiao F, Zhu J, Zhao L, Zheng G, Yang A, Tao J, Zhang B, Huang Z, Xiong F (2010) Involvement of pro-inflammatory and anti-inflammatory cytokines in the anti-inflammatory activity of Rubus idaeus L. on LPS-treated RAW 264.7 cells. J Chin Pharm Sci 19:201–208

    Google Scholar 

  156. Martinez-Ferrer M, Iturregui JM, Uwamariya C, Starkman J, Sharif-Afshar AR, Suzuki K, Visedsindh W, Matusik RJ, Dmochowski RR, Bhowmick NA (2008) Role of nicotinic and estrogen signaling during experimental acute and chronic bladder inflammation. Am J Pathol 172:59–67

    Article  CAS  PubMed  Google Scholar 

  157. Sawe N, Steinberg G, Zhao H (2008) Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. J Neurosci Res 86:1659–1669

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr. David Hosford and Beth Fordham-Meier for their insightful review and suggestions that contributed significantly to the quality of the manuscript.

Author information

Authors and Affiliations

  1. Preclinical Research, Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, NC, 27101, USA

    Merouane Bencherif & Patrick M. Lippiello

  2. Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA, 30912, USA

    Rudolf Lucas & Mario B. Marrero

Authors
  1. Merouane Bencherif
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick M. Lippiello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rudolf Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mario B. Marrero
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Merouane Bencherif.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bencherif, M., Lippiello, P.M., Lucas, R. et al. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell. Mol. Life Sci. 68, 931–949 (2011). https://doi.org/10.1007/s00018-010-0525-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0525-1

Keywords

Search

Navigation