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Dopamine mediates vagal modulation of the immune system by electroacupuncture

Abstract

Previous anti-inflammatory strategies against sepsis, a leading cause of death in hospitals, had limited efficacy in clinical trials, in part because they targeted single cytokines and the experimental models failed to mimic clinical settings1,2,3. Neuronal networks represent physiological mechanisms, selected by evolution to control inflammation, that can be exploited for the treatment of inflammatory and infectious disorders3. Here, we report that sciatic nerve activation with electroacupuncture controls systemic inflammation and rescues mice from polymicrobial peritonitis. Electroacupuncture at the sciatic nerve controls systemic inflammation by inducing vagal activation of aromatic L-amino acid decarboxylase, leading to the production of dopamine in the adrenal medulla. Experimental models with adrenolectomized mice mimic clinical adrenal insufficiency4, increase the susceptibility to sepsis and prevent the anti-inflammatory effects of electroacupuncture. Dopamine inhibits cytokine production via dopamine type 1 (D1) receptors. D1 receptor agonists suppress systemic inflammation and rescue mice with adrenal insufficiency from polymicrobial peritonitis. Our results suggest a new anti-inflammatory mechanism mediated by the sciatic and vagus nerves that modulates the production of catecholamines in the adrenal glands. From a pharmacological perspective, the effects of selective dopamine agonists mimic the anti-inflammatory effects of electroacupuncture and can provide therapeutic advantages to control inflammation in infectious and inflammatory disorders.

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Figure 1: Electroacupuncture controls systemic inflammation in sepsis via the sciatic and vagus nerves and catecholamines from the adrenal glands.
Figure 2: Electroacupuncture induces the expression of DOPA decarboxylase and dopamine.
Figure 3: Electroacupuncture rescues mice from established polymicrobial peritonitis.
Figure 4: D1 receptor agonist rescues mice from established polymicrobial peritonitis with adrenal insufficiency.

References

  1. Angus, D.C. & van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Annane, D. Adrenal insufficiency in sepsis. Curr. Pharm. Des. 14, 1882–1886 (2008).

    CAS  Article  Google Scholar 

  5. Tracey, K.J. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664 (1987).

    CAS  Article  Google Scholar 

  6. Riedemann, N.C., Guo, R.F. & Ward, P.A. Novel strategies for the treatment of sepsis. Nat. Med. 9, 517–524 (2003).

    CAS  Article  Google Scholar 

  7. Ulloa, L., Brunner, M., Ramos, L. & Deitch, E.A. Scientific and clinical challenges in sepsis. Curr. Pharm. Des. 15, 1918–1935 (2009).

    CAS  Article  Google Scholar 

  8. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).

    CAS  Article  Google Scholar 

  9. Abraham, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit. Care Med. 29, 503–510 (2001).

    CAS  Article  Google Scholar 

  10. Borovikova, L.V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to LPS. Nature 405, 458–462 (2000).

    CAS  Article  Google Scholar 

  11. Huston, J.M. et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203, 1623–1628 (2006).

    CAS  Article  Google Scholar 

  12. Peña, G. et al. Cholinergic regulatory lymphocytes re-establish neuromodulation of innate immune responses in sepsis. J. Immunol. 187, 718–725 (2011).

    Article  Google Scholar 

  13. Bernik, T.R. et al. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J. Vasc. Surg. 36, 1231–1236 (2002).

    Article  Google Scholar 

  14. Altavilla, D. et al. Activation of the cholinergic anti-inflammatory pathway reduces NF-kappab activation, blunts TNF-α production, and protects againts splanchic artery occlusion shock. Shock 25, 500–506 (2006).

    CAS  Article  Google Scholar 

  15. Cai, B. et al. α7 cholinergic-agonist prevents systemic inflammation and improves survival during resuscitation. J. Cell. Mol. Med. 13, 3774–3785 (2009).

    Article  Google Scholar 

  16. van Westerloo, D.J. et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 130, 1822–1830 (2006).

    CAS  Article  Google Scholar 

  17. Pullan, R.D. et al. Transdermal nicotine for active ulcerative colitis. N. Engl. J. Med. 330, 811–815 (1994).

    CAS  Article  Google Scholar 

  18. Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med. 10, 1216–1221 (2004).

    CAS  Article  Google Scholar 

  19. van Westerloo, D.J. et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 191, 2138–2148 (2005).

    CAS  Article  Google Scholar 

  20. Vickers, A.J. et al. Acupuncture for chronic pain: individual patient data meta-analysis. Arch. Intern. Med. 172, 1444–1453 (2012).

    Article  Google Scholar 

  21. Lee, A. & Done, M.L. Stimulation of the wrist acupuncture point P6 for preventing postoperative nausea and vomiting. Cochrane Database Syst. Rev. CD003281 (2004).

  22. Napadow, V. & Kaptchuk, T.J. Patient characteristics for outpatient acupuncture in Beijing, China. J. Altern. Complement. Med. 10, 565–572 (2004).

    Article  Google Scholar 

  23. Wu, H.M. et al. Acupuncture for stroke rehabilitation. Cochrane Database Syst. Rev. CD004131 (2006).

  24. Goldman, N. et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat. Neurosci. 13, 883–888 (2010).

    CAS  Article  Google Scholar 

  25. Ernst, E., Lee, M.S. & Choi, T.Y. Acupuncture: does it alleviate pain and are there serious risks? A review of reviews. Pain 152, 755–764 (2011).

    CAS  Article  Google Scholar 

  26. Vida, G. et al. β2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. FASEB J. 25, 4476–4485 (2011).

    CAS  Article  Google Scholar 

  27. Coupland, R.E., Parker, T.L., Kesse, W.K. & Mohamed, A.A. The innervation of the adrenal gland. III. Vagal innervation. J. Anat. 163, 173–181 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    CAS  Article  Google Scholar 

  29. Vida, G., Peña, G., Deitch, E.A. & Ulloa, L. α7-nicotinic receptor mediates vagal induction of splenic norepinephrine. J. Immunol. 186, 4340–4346 (2011).

    CAS  Article  Google Scholar 

  30. Grenader, A. & Healy, D.P. Fenoldopam is a partial agonist at dopamine-1 (DA1) receptors in LLC-PK1 cells. J. Pharmacol. Exp. Ther. 258, 193–198 (1991).

    CAS  PubMed  Google Scholar 

  31. Weber, R.R. et al. Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients. Br. J. Clin. Pharmacol. 25, 17–21 (1988).

    CAS  Article  Google Scholar 

  32. Denef, C., Manet, D. & Dewals, R. Dopaminergic stimulation of prolactin release. Nature 285, 243–246 (1980).

    CAS  Article  Google Scholar 

  33. Gorissen, H. & Laduron, P. Solubilisation of high-affinity dopamine receptors. Nature 279, 72–74 (1979).

    CAS  Article  Google Scholar 

  34. Morelli, A. et al. Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo-controlled pilot trial. Crit. Care Med. 33, 2451–2456 (2005).

    CAS  Article  Google Scholar 

  35. Sorkin, L.S. & Yaksh, T.L. Behavioral models of pain states evoked by physical injury to the peripheral nerve. Neurotherapeutics 6, 609–619 (2009).

    Article  Google Scholar 

  36. Richner, M., Bjerrum, O.J., Nykjaer, A. & Vaegter, C.B. The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J. Vis. Exp. 3092 (2011).

  37. Kadl, A., Pontiller, J., Exner, M. & Leitinger, N. Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia. Shock 28, 582–588 (2007).

    CAS  PubMed  Google Scholar 

  38. Panayotis, N. et al. Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. Neurobiol. Dis. 41, 385–397 (2011).

    CAS  Article  Google Scholar 

  39. Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397, 710–713 (1999).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank P. Morcillo, J.M. Inclan-Rico and J.R. Berlin for their comments and suggestions and M. Marks (University of Colorado) and B. Kobilka (Stanford University) for the α7nAChR and β2AR knockout mice. R.T.-R. was supported by the University Autónoma Benito Juarez de Oaxaca. M.d.R.T.-B. was supported by the Mexican National Council for Science and Technology. L.U. is supported by the faculty program of the Department of Surgery of the New Jersey Medical School, the Foundation of University of Medicine and Dentistry of New Jersey and US National Institutes of Health grant RO1-GM084125.

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R.T.-R., G.Y., G.P., P.M. and M.d.R.T.-B. performed the experiments, prepared the figures and revised the article. M.A.M.-E., L.A.A.-P. and A.I. contributed to the design of the study and revised the paper. L.U. designed and directed the study and wrote the paper.

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Correspondence to Luis Ulloa.

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Torres-Rosas, R., Yehia, G., Peña, G. et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 20, 291–295 (2014). https://doi.org/10.1038/nm.3479

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