Molecular Medicine

, Volume 18, Issue 3, pp 539–543 | Cite as

α7 Nicotinic Acetylcholine Receptor (α7nAChR) Expression in Bone Marrow-Derived Non-T Cells Is Required for the Inflammatory Reflex

  • Peder S Olofsson
  • David A Katz
  • Mauricio Rosas-Ballina
  • Yaakov A Levine
  • Mahendar Ochani
  • Sergio I Valdés-Ferrer
  • Valentin A Pavlov
  • Kevin J Tracey
  • Sangeeta S Chavan
Research Article


The immune response to infection or injury coordinates host defense and tissue repair, but also has the capacity to damage host tissues. Recent advances in understanding protective mechanisms have found neural circuits that suppress release of damaging cytokines. Stimulation of the vagus nerve protects from excessive cytokine production and ameliorates experimental inflammatory disease. This mechanism, the inflammatory reflex, requires the α7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel expressed on macrophages, lymphocytes, neurons and other cells. To investigate cell-specific function of α7nAChR in the inflammatory reflex, we created chimeric mice by cross-transferring bone marrow between wild-type (WT) and α7nAChR-deficient mice. Deficiency of α7nAChR in bone marrow-derived cells significantly impaired vagus nerve-mediated regulation of tumor necrosis factor (TNF), whereas α7nAChR deficiency in neurons and other cells had no significant effect. In agreement with recent work, the inflammatory reflex was not functional in nude mice, because functional T cells are required for the integrity of the pathway. To investigate the role of T-cell α7nAChR, we adoptively transferred α7nAChR-deficient or WT T cells to nude mice. Transfer of WT and α7nAChR-deficient T cells restored function, indicating that α7nAChR expression on T cells is not necessary for this pathway. Together, these results indicate that α7nAChR expression in bone marrow-derived non-T cells is required for the integrity of the inflammatory reflex.



This work was supported in part by grants from National Institute of General Medical Sciences, National Institutes of Health (NIGMS, NIH; GM57226 and 3R01GM057226-10S1) to KJ Tracey and from the Wenner-Gren Foundations in Stockholm to PS Olofsson.


  1. 1.
    Tracey KJ. (2009) Reflex control of immunity. Nat. Rev. Immunol. 9:418–28.CrossRefGoogle Scholar
  2. 2.
    Matsunaga K, Klein TW, Friedman H, Yamamoto Y. (2001) Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J. Immunol. 167:6518–24.CrossRefGoogle Scholar
  3. 3.
    Orr-Urtreger A, Kedmi M, Rosner S, Karmeli F, Rachmilewitz D. (2005) Increased severity of experimental colitis in alpha 5 nicotinic acetyl-choline receptor subunit-deficient mice. Neuro-report. 16:1123–7.Google Scholar
  4. 4.
    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. 28:700–3.PubMedGoogle Scholar
  5. 5.
    Pavlov VA, et al. (2007) Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med. 35:1139–44.CrossRefGoogle Scholar
  6. 6.
    Yeboah MM, et al. (2008) Cholinergic agonists attenuate renal ischemia-reperfusion injury in rats. Kidney Int. 74:62–9.CrossRefGoogle Scholar
  7. 7.
    van Maanen MA, et al. (2009) Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum. 60:114–122.CrossRefGoogle Scholar
  8. 8.
    Rosas-Ballina M, et al. (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.CrossRefGoogle Scholar
  9. 9.
    Karimi K, Bienenstock J, Wang L, Forsythe P. (2010) The vagus nerve modulates CD4+ T cell activity. Brain Behav. Immun. 24:316–23.CrossRefGoogle Scholar
  10. 10.
    Steinman L. (2004) Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5:575–81.CrossRefGoogle Scholar
  11. 11.
    Rosas-Ballina M, Tracey KJ. (2009) The neurology of the immune system: neural reflexes regulate immunity. Neuron. 64:28–32.CrossRefGoogle Scholar
  12. 12.
    Sun J, Singh V, Kajino-Sakamoto R, Aballay A. (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science. 332:729–32.CrossRefGoogle Scholar
  13. 13.
    Borovikova LV, et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 405:458–62.CrossRefGoogle Scholar
  14. 14.
    Tracey KJ. (2002) The inflammatory reflex. Nature. 420:853–9.CrossRefGoogle Scholar
  15. 15.
    Rosas-Ballina M, et al. (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 334:98–101.CrossRefGoogle Scholar
  16. 16.
    Wang H, et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 421:384–8.CrossRefGoogle Scholar
  17. 17.
    Parrish WR, et al. (2008) Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol. Med. 14:567–74.CrossRefGoogle Scholar
  18. 18.
    Kawashima K, Fujii T. (2004) Expression of nonneuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front Biosci. 9:2063–85.CrossRefGoogle Scholar
  19. 19.
    Guarda G, et al. (2009) T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature. 460:269–73.CrossRefGoogle Scholar
  20. 20.
    Kim KD, et al. (2007) Adaptive immune cells temper initial innate responses. Nat. Med. 13:1248–52.CrossRefGoogle Scholar
  21. 21.
    Tracey KJ. (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin. Invest. 117:289–96.CrossRefGoogle Scholar
  22. 22.
    Huston JM, et al. (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203:1623–8.CrossRefGoogle Scholar
  23. 23.
    Broide RS, Leslie FM. (1999) The alpha7 nicotinic acetylcholine receptor in neuronal plasticity. Mol. Neurohiol. 20:1–16.CrossRefGoogle Scholar
  24. 24.
    Lips KS, Konig P, Schatzle K, et al. (2006) Coex-pression and spatial association of nicotinic acetyl-choline receptor subunits alpha7 and alpha10 in rat sympathetic neurons. J Mol. Neurosci. 30:15–6.CrossRefGoogle Scholar
  25. 25.
    Bellinger DL, Lorton D, Hamill RW, Felten SY, Felten DL. (1993) Acetylcholinesterase staining and choline acetyltransferase activity in the young adult rat spleen: lack of evidence for cholinergic innervation. Brain Behav. Immun. 7:191–204.CrossRefGoogle Scholar
  26. 26.
    Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. (2003) The cholinergic anti-inflammatory pathway: a missing link in neuroim-munomodulation. Mol. Med. 9:125–34.CrossRefGoogle Scholar
  27. 27.
    Bencherif M, Lippiello PM, Lucas R, Marrero MB. (2011) Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell. Mol. Life Sci. 68:931–49.CrossRefGoogle Scholar

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Authors and Affiliations

  • Peder S Olofsson
    • 1
  • David A Katz
    • 1
  • Mauricio Rosas-Ballina
    • 1
  • Yaakov A Levine
    • 2
  • Mahendar Ochani
    • 1
  • Sergio I Valdés-Ferrer
    • 1
  • Valentin A Pavlov
    • 1
  • Kevin J Tracey
    • 1
  • Sangeeta S Chavan
    • 1
  1. 1.Laboratory of Biomedical ScienceThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Setpoint Medical CorporationValenciaUSA

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