Anti-inflammatory reflex - interaction of the nervous system and the immune system

Document Type : Analytic Review

Author
Department of Physiology-Pharmacology-Medical Physics, Faculty of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
Abstract
The coordination of body systems is important for overcoming various conditions. The nervous system, as a fast coordinator of the body, reflexively manages many functions. At the same time, the immune system is involved in endogenous and exogenous factors that disturb homeostasis at any time to protect the body. Research has shown negative feedback between the two systems. Inflammatory factors such as pro-inflammatory cytokines stimulate the vagus nerve, which increases afferent signals to the central nervous system. The central autonomic network increases efferent vagus nerve impulses. Amplification of efferent vagus nerve activity promotes the release of acetylcholine. Increased acetylcholine suppresses inflammation through its receptors on immune cells. The aforementioned feedback process, which is the two-way communication of the nervous and immune systems, is called the "anti-inflammatory reflex". In the present article, the role of each component and the therapeutic potential of using the anti-inflammatory reflex will be discussed. Moreover, heart rate variability as an index for measuring the state of the anti-inflammatory reflex is considered.

Keywords


1. Michael-Titus AT, Shortland P. The Nervous System: The Nervous System, E-Book. Elsevier Health Sciences; 2022.
2. Somjen G. Sensory coding in the mammalian nervous system. 2013.
3. Park KS. Nervous System. Humans and Electricity: Understanding Body Electricity and Applications. Springer; 2023. p. 27-51.
4. Ansar W, Ghosh S, Ansar W, Ghosh S. Inflammation and inflammatory diseases, markers, and mediators: Role of CRP in some inflammatory diseases. Biology of C reactive protein in health and disease. 2016:67-107.
5. Johnkennedy N, Mercy OC. Perspective of Inflammation and Inflammation Markers. Journal La Medihealtico. 2022;3(1):16-26.
6. Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutrition reviews. 2007;65(suppl_3):S140-S46.
7. Megari K. Quality of life in chronic disease patients. Health psychology research. 2013;1(3).
8. Gulati K, Guhathakurta S, Joshi J, Rai N, Ray A. Cytokines and their role in health and disease: a brief overview. Moj Immunol. 2016;4(2):00121.
9. Kany S, Vollrath JT, Relja B. Cytokines in inflammatory disease. International journal of molecular sciences. 2019;20(23):6008.
10. O'Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity. 2008;28(4):477-87.
11. De Jong HK, Van Der Poll T, Wiersinga WJ. The systemic pro-inflammatory response in sepsis. Journal of innate immunity. 2010;2(5):422-30.
12. Jaffer U, Wade R, Gourlay T. Cytokines in the systemic inflammatory response syndrome: a review. HSR proceedings in intensive care & cardiovascular anesthesia. 2010;2(3):161.
13. Fajgenbaum DC, June CH. Cytokine storm. New England Journal of Medicine. 2020;383(23):2255-73.
14. Sygitowicz G, Sitkiewicz D. Molecular mechanisms of organ damage in sepsis: an overview. Brazilian Journal of Infectious Diseases. 2021;24:552-60.
15. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853-59.
16. Hopkins SJ. Central nervous system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed. 2007;78(Suppl 1):231-47.
17. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-62.
18. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun. 2005 Nov;19(6):493-9.
19. Hoover DB. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacology & therapeutics. 2017;179:1-16.
20. Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, et al. The interplay between autonomic nervous system and inflammation across systemic autoimmune diseases. International Journal of Molecular Sciences. 2022;23(5):2449.
21. Bonaz B, Sinniger V, Pellissier S. Therapeutic potential of vagus nerve stimulation for inflammatory bowel diseases. Frontiers in neuroscience. 2021;15:650971.
22. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nature Reviews Endocrinology. 2012;8(12):743-54.
23. Komegae EN, Farmer DGS, Brooks VL, McKinley MJ, McAllen RM, Martelli D. Vagal afferent activation suppresses systemic inflammation via the splanchnic anti-inflammatory pathway. Brain, behavior, and immunity. 2018;73:441-49.
24. Akira S. Toll-like receptors and innate immunity. Advances in immunology. 2001;78:1-56.
25. Karlsson H, Larsson P, Wold AE, Rudin A. Pattern of cytokine responses to gram‐positive and gram‐negative commensal bacteria is profoundly changed when monocytes differentiate into dendritic cells. Scandinavian Journal of Immunology. 2004;59(6):628-28.
26. Tietze K, Dalpke A, Morath S, Mutters R, Heeg K, Nonnenmacher C. Differences in innate immune responses upon stimulation with gram‐positive and gram‐negative bacteria. Journal of periodontal research. 2006;41(5):447-54.
27. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nature Reviews Immunology. 2006;6(4):318-28.
28. Matsuda A, Jacob A, Wu R, Aziz M, Yang W-L, Matsutani T, et al. Novel therapeutic targets for sepsis: regulation of exaggerated inflammatory responses. Journal of Nippon Medical School. 2012;79(1):4-18.
29. Johnston G, Webster N. Cytokines and the immunomodulatory function of the vagus nerve. British journal of anaesthesia. 2009;102(4):453-62.
30. Bonaz B, Sinniger V, Pellissier S. Anti‐inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. The Journal of physiology. 2016;594(20):5781-90.
31. Maier SF, Goehler LE, Fleshner M, Watkins LR. The role of the vagus nerve in cytokine‐to‐brain communication. Annals of the New York Academy of Sciences. 1998;840(1):289-300.
32. Maharjan A. Neuromodulation of the human autonomic nervous system using peripheral nerve stimulation techniques. University of Otago; 2022.
33. Garrett L, Trümbach D, Spielmann N, Wurst W, Fuchs H, Gailus-Durner V, et al. A rationale for considering heart/brain axis control in neuropsychiatric disease. Mammalian Genome. 2023;34(2):331-50.
34. Tanaka S, Hammond B, Rosin DL, Okusa MD. Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway. Bioelectronic medicine. 2019;5(1):13.
35. Pavlov VA, Tracey KJ. Neural circuitry and immunity. Immunologic research. 2015;63:38-57.
36. Matusik PS, Zhong C, Matusik PT, Alomar O, Stein PK. Neuroimaging studies of the neural correlates of heart rate variability: a systematic review. Journal of clinical medicine. 2023;12(3):1016.
37. Quadt L, Critchley H, Nagai Y. Cognition, emotion, and the central autonomic network. Autonomic Neuroscience. 2022;238:102948.
38. Rosas‐Ballina M, Tracey K. Cholinergic control of inflammation. Journal of internal medicine. 2009;265(6):663-79.
39. Van Der Zanden EP, Boeckxstaens GE, De Jonge WJ. The vagus nerve as a modulator of intestinal inflammation. Neurogastroenterology & Motility. 2009;21(1):6-17.
40. Metz CN, Pavlov VA. Vagus nerve cholinergic circuitry to the liver and the gastrointestinal tract in the neuroimmune communicatome. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2018;315(5):G651-G58.
41. Zdanowski R, Krzyżowska M, Ujazdowska D, Lewicka A, Lewicki S. Role of α7 nicotinic receptor in the immune system and intracellular signaling pathways. Central European Journal of Immunology. 2015;40(3):373-79.
42. Chao R, Tong Y-l, Li J-c, Lu Z-q, Yao Y-m. The protective effect of alpha 7 nicotinic acetylcholine receptor activation on critical illness and its mechanism. International journal of biological sciences. 2017;13(1):46.
43. Ren C, Li X-h, Wang S-b, Wang L-x, Dong N, Wu Y, et al. Activation of central alpha 7 nicotinic acetylcholine receptor reverses suppressed immune function of T lymphocytes and protects against sepsis lethality. International Journal of Biological Sciences. 2018;14(7):748.
44. Mazloom R, Eftekhari G, Rahimi-Balaei M, Khori V, Hajizadeh S, Dehpour AR, et al. The role of α7 nicotinic acetylcholine receptor in modulation of heart rate dynamics in endotoxemic rats. PLoS One. 2013;8(12):e82251.
45. Wu Y-j, Wang L, Ji C-f, Gu S-f, Yin Q, Zuo J. The role of α7nAChR-mediated cholinergic anti-inflammatory pathway in immune cells. Inflammation. 2021;44(3):821-34.
46. Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol. 2015;6:171.
47. Pavlov VA. Collateral benefits of studying the vagus nerve in bioelectronic medicine. Bioelectron Med. 2019;5:5.
48. Durand M, Hagimont E, Louis H, Asfar P, Frippiat JP, Singer M, et al. The β 1 -Adrenergic Receptor Contributes to Sepsis-Induced Immunosuppression Through Modulation of Regulatory T-Cell Inhibitory Function. Crit Care Med. 2022 Sep 1;50(9):e707-e18.
49. McAllen RM, McKinley MJ, Martelli D. Reflex regulation of systemic inflammation by the autonomic nervous system. Auton Neurosci. 2022 Jan;237:102926.
50. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003;9(1):3-24.
51. DeMorrow S. Role of the Hypothalamic-Pituitary-Adrenal Axis in Health and Disease. Int J Mol Sci. 2018 Mar 26;19(4).
52. Miller WL. The Hypothalamic-Pituitary-Adrenal Axis: A Brief History. Horm Res Paediatr. 2018;89(4):212-23.
53. Boeckxstaens G. The clinical importance of the anti-inflammatory vagovagal reflex. Handb Clin Neurol. 2013;117:119-34.
54. Kelly MJ, Breathnach C, Tracey KJ, Donnelly SC. Manipulation of the inflammatory reflex as a therapeutic strategy. Cell Rep Med. 2022 Jul 19;3(7):100696.
55. Esmaeeli Dehaj H, Maleki Dehnavi S, Zahedi Nejad M, Akbarzadeh Kolahi S, Abdolghaffari AH, Khalili A, et al. The time interval between injection of nicotine and tremor initiation: a new index for evaluating nicotine efficacy in rodents. Toxicol Mech Methods. 2023 Dec 13:1-5.
56. Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med. 2017 Jul;282(1):64-75.
57. Aranow C, Atish-Fregoso Y, Lesser M, Mackay M, Anderson E, Chavan S, et al. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, sham-controlled pilot trial. Ann Rheum Dis. 2021 Feb;80(2):203-08.
58. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007 Feb;117(2):289-96.
59. Camm AJ, Malik M, Bigger JT, Breithardt G, Cerutti S, Cohen RJ, et al. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93(5):1043-65.
60. Tiwari R, Kumar R, Malik S, Raj T, Kumar P. Analysis of Heart Rate Variability and Implication of Different Factors on Heart Rate Variability. Curr Cardiol Rev. 2021;17(5):e160721189770.
61. Scheff JD, Griffel B, Corbett SA, Calvano SE, Androulakis IP. On heart rate variability and autonomic activity in homeostasis and in systemic inflammation. Math Biosci. 2014 Jun;252:36-44.
62. Mol MBA, Strous MTA, van Osch FHM, Vogelaar FJ, Barten DG, Farchi M, et al. Heart-rate-variability (HRV), predicts outcomes in COVID-19. PLoS One. 2021;16(10):e0258841.
63. Billman GE. Heart rate variability–a historical perspective. Frontiers in physiology. 2011;2:86.
64. Gholami M, Mazaheri P, Mohamadi A, Dehpour T, Safari F, Hajizadeh S, et al. Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats. Shock. 2012 Feb;37(2):219-27.
65. Mazloom R, Shirazi AH, Hajizadeh S, Dehpour AR, Mani AR. The effect of endotoxin on the controllability of cardiac rhythm in rats. Physiol Meas. 2014 Mar;35(3):339-49.