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The Interactions of the Immune System and the Brain in Hypertension

  • Secondary Hypertension: Nervous System Mechanisms (M Wyss, Section Editor)
  • Published:
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Abstract

Purpose of Review

Hypertension still represents a huge health problem, causing death and disability and rising at epidemic levels worldwide. The availability of a vast array of antihypertensive therapeutic strategies still fails to adequately treat significant fractions of refractory patients. The possible explanation to this disappointing evidence should be ascribed to the fact that myriad of mechanisms contribute to onset and maintenance of hypertension. Although we have been able to develop strategies aimed at counteracting the single mechanisms identified as master regulators of blood pressure, we still lack strategies capable to approach at the complex interactions established among the different pathophysiological mechanisms.

Recent Findings

One of the most intriguing pathophysiological interactions in hypertension emerged in the very last years is the one established between the autonomic nervous system and immunity.

Summary

Here we briefly review the most important contributions revealing neural modulation of immunity in hypertension and how this novel concept is integrated in the already known multitude of regulations exerted by the autonomic nervous system in typical organs involved in blood pressure regulation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Coffman TM. Under pressure: the search for the essential mechanisms of hypertension. Nat Med. 2011;17(11):1402–9. https://doi.org/10.1038/nm.2541.

    Article  CAS  PubMed  Google Scholar 

  2. Chobanian AV. Shattuck Lecture. The hypertension paradox—more uncontrolled disease despite improved therapy. N Engl J Med. 2009;361(9):878–87. https://doi.org/10.1056/NEJMsa0903829.

    Article  CAS  PubMed  Google Scholar 

  3. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2017:HYP.0000000000000065. https://doi.org/10.1161/HYP.0000000000000065.

  4. Banegas JR, Ruilope LM, de la Sierra A, de la Cruz JJ, Gorostidi M, Segura J, et al. High prevalence of masked uncontrolled hypertension in people with treated hypertension. Eur Heart J. 2014;35(46):3304–12. https://doi.org/10.1093/eurheartj/ehu016.

    Article  CAS  PubMed  Google Scholar 

  5. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory hypertension: evidence of heightened sympathetic activity as a cause of antihypertensive treatment failure. Hypertension. 2015;66(1):126–33. https://doi.org/10.1161/HYPERTENSIONAHA.115.05449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Harrison DG. The mosaic theory revisited: common molecular mechanisms coordinating diverse organ and cellular events in hypertension. J Am Soc Hypertens. 2013;7(1):68–74. https://doi.org/10.1016/j.jash.2012.11.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204(10):2449–60. https://doi.org/10.1084/jem.20070657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res. 2017;113(9):1009–23. https://doi.org/10.1093/cvr/cvx108.

    Article  PubMed  Google Scholar 

  9. Trott DW, Harrison DG. The immune system in hypertension. Adv Physiol Educ. 2014;38(1):20–4. https://doi.org/10.1152/advan.00063.2013.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mattson DL. Infiltrating immune cells in the kidney in salt-sensitive hypertension and renal injury. Am J Physiol Renal Physiol. 2014;307(5):F499–508. https://doi.org/10.1152/ajprenal.00258.2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. • Carnevale D, Pallante F, Fardella V, Fardella S, Iacobucci R, Federici M, et al. The angiogenic factor PlGF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. Immunity. 2014;41(5):737–52. https://doi.org/10.1016/j.immuni.2014.11.002. This paper presents a previously unknown role of the spleen in hypertension, where a growth factor mediates a neuroimmune interaction necessary for priming of adaptive immunity.

  12. Ordovas-Montanes J, Rakoff-Nahoum S, Huang S, Riol-Blanco L, Barreiro O, von Andrian UH. The regulation of immunological processes by peripheral neurons in homeostasis and disease. Trends Immunol. 2015;36(10):578–604. https://doi.org/10.1016/j.it.2015.08.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. • Chavan SS, Pavlov VA, Tracey KJ. Mechanisms and therapeutic relevance of neuro-immune communication. Immunity. 2017;46(6):927–42. https://doi.org/10.1016/j.immuni.2017.06.008. This review proposes a detailed examination of neuroimmune mechanisms described in several pathophysiological contexts, posing the accent of the related translational perspectives.

    Article  CAS  PubMed  Google Scholar 

  14. Rosas-Ballina M, Tracey KJ. The neurology of the immune system: neural reflexes regulate immunity. Neuron. 2009;64(1):28–32. https://doi.org/10.1016/j.neuron.2009.09.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7(5):335–46. https://doi.org/10.1038/nrn1902.

    Article  CAS  PubMed  Google Scholar 

  16. Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90(2):513–57. https://doi.org/10.1152/physrev.00007.2009.

    Article  CAS  PubMed  Google Scholar 

  17. Osborn JW, Kuroki MT. Sympathetic signatures of cardiovascular disease: a blueprint for development of targeted sympathetic ablation therapies. Hypertension. 2012;59(3):545–7. https://doi.org/10.1161/HYPERTENSIONAHA.111.182899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Esler M. The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp Physiol. 2011;96(7):611–22. https://doi.org/10.1113/expphysiol.2011.052332.

    PubMed  Google Scholar 

  19. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens. 2010;23(10):1052–60. https://doi.org/10.1038/ajh.2010.154.

    Article  PubMed  Google Scholar 

  20. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139(9):761–76. https://doi.org/10.7326/0003-4819-139-9-200311040-00011.

    Article  CAS  PubMed  Google Scholar 

  21. Marvar PJ, Harrison DG. Stress-dependent hypertension and the role of T lymphocytes. Exp Physiol. 2012;97(11):1161–7. https://doi.org/10.1113/expphysiol.2011.061507.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Esler M. The sympathetic nervous system in hypertension: back to the future? Curr Hypertens Rep. 2015;17(2):11. https://doi.org/10.1007/s11906-014-0519-8.

    Article  PubMed  Google Scholar 

  23. Grassi G, Colombo M, Seravalle G, Spaziani D, Mancia G. Dissociation between muscle and skin sympathetic nerve activity in essential hypertension, obesity, and congestive heart failure. Hypertension. 1998;31(1):64–7. https://doi.org/10.1161/01.HYP.31.1.64.

    Article  CAS  PubMed  Google Scholar 

  24. Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking G, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11(1):3–20. https://doi.org/10.1161/01.HYP.11.1.3.

    Article  CAS  PubMed  Google Scholar 

  25. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. Hypertension. 1989;14(2):177–83. https://doi.org/10.1161/01.HYP.14.2.177.

    Article  CAS  PubMed  Google Scholar 

  26. Lembo G, Napoli R, Capaldo B, Rendina V, Iaccarino G, Volpe M, et al. Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension. J Clin Invest. 1992;90(1):24–9. https://doi.org/10.1172/JCI115842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rumantir MS, Vaz M, Jennings GL, Collier G, Kaye DM, Seals DR, et al. Neural mechanisms in human obesity-related hypertension. J Hypertens. 1999;17(8):1125–33. https://doi.org/10.1097/00004872-199917080-00012.

  28. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77(1):75–197. https://doi.org/10.1152/physrev.1997.77.1.75.

    Article  CAS  PubMed  Google Scholar 

  29. Osborn JW, Fink GD. Region-specific changes in sympathetic nerve activity in angiotensin II-salt hypertension in the rat. Exp Physiol. 2010;95(1):61–8. https://doi.org/10.1113/expphysiol.2008.046326.

    Article  CAS  PubMed  Google Scholar 

  30. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478–84. https://doi.org/10.1016/S0140-6736(97)11144-8.

    Article  PubMed  Google Scholar 

  31. Abboud FM. The Walter B. Cannon Memorial Award Lecture, 2009. Physiology in perspective: the wisdom of the body. In search of autonomic balance: the good, the bad, and the ugly. Am J Physiol Regul Integr Comp Physiol. 2010;298(6):R1449–67. https://doi.org/10.1152/ajpregu.00130.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun. 2007;21(6):736–45. https://doi.org/10.1016/j.bbi.2007.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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. https://doi.org/10.1038/35013070.

    Article  CAS  PubMed  Google Scholar 

  34. Rosas-Ballina M, Ochani M, Parrish WR, Ochani K, Harris YT, Huston JM, et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc Natl Acad Sci U S A. 2008;105(31):11008–13. https://doi.org/10.1073/pnas.0803237105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98–101. https://doi.org/10.1126/science.1209985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384–8. https://doi.org/10.1038/nature01339.

  37. Bhatt DL, Kandzari DE, O'Neill WW, D'Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393–401. https://doi.org/10.1056/NEJMoa1402670.

    Article  CAS  PubMed  Google Scholar 

  38. • Esler M. Renal denervation for treatment of drug-resistant hypertension. Trends Cardiovasc Med. 2015;25(2):107–15. https://doi.org/10.1016/j.tcm.2014.09.014. This review proposes an updated analysis of the state-of-the-art of renal denervation treatment of hypertension.

    Article  PubMed  Google Scholar 

  39. • Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, et al. Renal denervation prevents immune cell activation and renal inflammation in angiotensin II-induced hypertension. Circ Res. 2015;117(6):547–57. https://doi.org/10.1161/CIRCRESAHA.115.306010. This work reports important results related to the effect of renal denervation on immune mechanisms in a murine model of AngII-induced hypertension. Renal innervation participates to dendritic cells activation, T-cell infiltration and end-organ damage in the kidneys contributing to the development of hypertension.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. • Banek CT, Knuepfer MM, Foss JD, Fiege JK, Asirvatham-Jeyaraj N, Van Helden D, et al. Resting afferent renal nerve discharge and renal inflammation: elucidating the role of afferent and efferent renal nerves in deoxycorticosterone acetate salt hypertension. Hypertension. 2016;68(6):1415–23. https://doi.org/10.1161/HYPERTENSIONAHA.116.07850. This paper presents important data describing the effects of renal denervation on immune mechanisms in kidney of mice chronically treated with deoxycorticosterone acetate to induce hypertension. This important work prospects a further way of looking at the sympathetic innervation in kidneys.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. • Carnevale D, Perrotta M, Pallante F, Fardella V, Iacobucci R, Fardella S, et al. A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nat Commun. 2016;7:13035. https://doi.org/10.1038/ncomms13035. This paper reports evidence of a novel component of the sympathetic outflow in hypertension identified by microneurography of the sympathetic splenic nerve in mice. The sympathetic splenic overdrive is activated in different models of hypertension at early time points after the challenges, thus supporting a mechanistic role in priming of immunity.

  42. Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand C, et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ Res. 2010;107(2):263–70. https://doi.org/10.1161/CIRCRESAHA.110.217299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ganta CK, Lu N, Helwig BG, Blecha F, Ganta RR, Zheng L, et al. Central angiotensin II-enhanced splenic cytokine gene expression is mediated by the sympathetic nervous system. Am J Physiol Heart Circ Physiol. 2005;289(4):H1683–91. https://doi.org/10.1152/ajpheart.00125.2005.

    Article  CAS  PubMed  Google Scholar 

  44. • Abboud FM, Harwani SC, Chapleau MW. Autonomic neural regulation of the immune system: implications for hypertension and cardiovascular disease. Hypertension. 2012;59(4):755–62. https://doi.org/10.1161/HYPERTENSIONAHA.111.186833. Provides an accurate review of interactions between the autonomic nervous system and immune system in cardiovascular diseases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Italian Ministry of Health “Ricerca Corrente.”

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Authors and Affiliations

  1. Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, 86077, Pozzilli, IS, Italy

    Marialuisa Perrotta, Giuseppe Lembo & Daniela Carnevale

  2. Department of Molecular Medicine, Sapienza University of Rome, 00161, Rome, Italy

    Giuseppe Lembo & Daniela Carnevale

Authors
  1. Marialuisa Perrotta
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  2. Giuseppe Lembo
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  3. Daniela Carnevale
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Correspondence to Daniela Carnevale.

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This article is part of the Topical Collection on Secondary Hypertension: Nervous System Mechanisms

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Perrotta, M., Lembo, G. & Carnevale, D. The Interactions of the Immune System and the Brain in Hypertension. Curr Hypertens Rep 20, 7 (2018). https://doi.org/10.1007/s11906-018-0808-8

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