Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Neuroimmune crosstalk in the pathophysiology of hypertension

Abstract

Hypertension is an important risk factor for cardiovascular morbidity and mortality and for events such as myocardial infarction, stroke, heart failure and chronic kidney disease and is a major determinant of disability-adjusted life-years. Despite the importance of hypertension, the pathogenesis of essential hypertension, which involves the complex interaction of several mechanisms, is still poorly understood. Evidence suggests that interplay between bone marrow, microglia and immune mediators underlies the development of arterial hypertension, in particular through mechanisms involving cytokines and peptides, such as neuropeptide Y, substance P, angiotensin II and angiotensin-(1–7). Chronic psychological stress also seems to have a role in increasing the risk of hypertension, probably through the activation of neuroimmune pathways. In this Review, we summarize the available data on the possible role of neuroimmune crosstalk in the origin and maintenance of arterial hypertension and discuss the implications of this crosstalk for recovery and rehabilitation after cardiac and cerebral injuries.

Key points

  • A proposed interplay between the bone marrow, microglia and immune mediators could underlie the development of arterial hypertension.

  • Brain microglia activation is a hallmark of neuroinflammation in hypertension; the bone marrow contributes to hypertension by increasing the extravasation of peripheral inflammatory cells into the brain.

  • Chronic psychological stress increases the risk of hypertension through a mechanism involving the bone marrow and sympathetic nervous system.

  • Cytokines, neuropeptides and peptides including neuropeptide Y, substance P, angiotensin II and angiotensin-(1–7) seem to act as messengers between immunity, the central nervous system and the cardiovascular system to regulate blood pressure homeostasis.

  • Genome-wide association studies have identified links between three pairs of genes related to inflammation and diastolic blood pressure and between BDNF (encoding a neurotrophic factor implicated in neuropeptide Y modulation) and hypertension.

  • Clinical evidence shows that neuroimmune factors are involved in changes in the regulation of the cardiovascular system underlying arterial hypertension.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Proposed interaction between the bone marrow, microglia and immune mediators in arterial hypertension.
Fig. 2: Interactions between ANGII, ANG-(1–7), NPY, substance P and the immune system in hypertension.
Fig. 3: Proposed link between stress-related hypertension and neuroinflammation.

References

  1. 1.

    Kumar, J. Epidemiology of hypertension. Clin. Queries Nephrol. 2, 56–61 (2013).

    Google Scholar 

  2. 2.

    Chobanian, A. V. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289, 2560–2571 (2003).

    CAS  Google Scholar 

  3. 3.

    Hoffmann, T. J. et al. Genome-wide association analyses using electronic health records identify new loci influencing blood pressure variation. Nat. Genet. 536, 41–47 (2016).

    Google Scholar 

  4. 4.

    Parati, G. Antihypertensive therapy in 2014: linking pathophysiology to antihypertensive treatment. Nat. Rev. Cardiol. 12, 77–79 (2015).

    CAS  PubMed  Google Scholar 

  5. 5.

    Navar, L. G. Counterpoint: activation of the intrarenal renin-angiotensin system is the dominant contributor to systemic hypertension. J. Appl. Physiol. 109, 1998–2000 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Esler, M., Lambert, E. & Schlaich, M. Point: chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension. J. Appl. Physiol. 109, 1996–1998 (2010).

    PubMed  Google Scholar 

  7. 7.

    Parati, G. & Esler, M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur. Heart J. 33, 1058–1066 (2012).

    CAS  PubMed  Google Scholar 

  8. 8.

    Versari, D., Daghini, E., Virdis, A., Ghiadoni, L. & Taddei, S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br. J. Pharmacol. 157, 527–536 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Marchesi, C., Paradis, P. & Schiffrin, E. L. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol. Sci. 29, 367–374 (2008).

    CAS  PubMed  Google Scholar 

  10. 10.

    Singh, M. V., Chapleau, M. W., Harwani, S. C. & Abboud, F. The immune system and hypertension. Immunol. Res. 59, 243–253 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Avolio, E. et al. Role of brain neuroinflammatory factors on hypertension in the spontaneously hypertensive rat. Neuroscience 375, 158–168 (2018).

    CAS  PubMed  Google Scholar 

  12. 12.

    Iulita, M. F. et al. Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice. J. Neuroinflamm. 15, 62 (2018).

    Google Scholar 

  13. 13.

    Wang, M. et al. Central blockade of NLRP3 reduces blood pressure via regulating inflammation microenvironment and neurohormonal excitation in salt-induced prehypertensive rats. J. Neuroinflamm. 15, 95 (2018).

    Google Scholar 

  14. 14.

    Yang, S. et al. Alpha 1-antitrypsin inhibits microglia activation and facilitates the survival of iPSC grafts in hypertension mouse model. Cell. Immunol. 328, 49–57 (2018).

    CAS  PubMed  Google Scholar 

  15. 15.

    Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).

    CAS  PubMed  Google Scholar 

  16. 16.

    Li, D. J. et al. Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension. Hypertension 57, 298–307 (2011).

    CAS  PubMed  Google Scholar 

  17. 17.

    Kapoor, K., Bhandare, A. M., Farnham, M. M. J. & Pilowsky, P. M. Alerted microglia and the sympathetic nervous system: a novel form of microglia in the development of hypertension. Respir. Physiol. Neurobiol. 226, 51–62 (2016).This paper provides evidence of changes in microglia related to changes in BP.

    CAS  PubMed  Google Scholar 

  18. 18.

    Zubcevic, J. et al. Functional neural-bone marrow pathways: Implications in hypertension and cardiovascular disease. Hypertension 63, 129–140 (2014).This paper is one of the main studies providing an explanation of the pathway connecting the bone marrow with microglia and hypertension.

    Google Scholar 

  19. 19.

    Kapoor, K. et al. Dynamic changes in the relationship of microglia to cardiovascular neurons in response to increases and decreases in blood pressure. Neuroscience 329, 12–29 (2016).

    CAS  PubMed  Google Scholar 

  20. 20.

    Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 19, 325–329 (2012).

    Google Scholar 

  21. 21.

    Santisteban, M. M. et al. Involvement of bone marrow cells and neuroinflammation in hypertension. Circ. Res. 117, 178–191 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zubcevic, J. et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension 63, 542–550 (2014).

    CAS  PubMed  Google Scholar 

  23. 23.

    Jun, J. Y. et al. Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension. Hypertension 60, 1316–1323 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Shi, P. et al. Brain microglial cytokines in neurogenic hypertension. Hypertension 56, 297–303 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ataka, K. et al. Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice. PLOS ONE 8, e81744 (2013).The authors of this article describe the crossing of the BBB by bone-marrow-derived cells in mice subjected to stress, suggesting unexpected neuroinflammatory effects of non-biochemical stimuli at the central level.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Santisteban, M. M., Zubcevic, J., Baekey, D. M. & Raizada, M. K. Dysfunctional brain-bone marrow communication: a paradigm shift in the pathophysiology of hypertension. Curr. Hypertens. Rep. 15, 377–389 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Soulet, D. & Rivest, S. Bone-marrow-derived microglia: myth or reality? Curr. Opin. Pharmacol. 8, 508–518 (2008).This Review summarizes evidence of bone-marrow-derived cells crossing the BBB and reviews controversial data.

    CAS  PubMed  Google Scholar 

  28. 28.

    Davoust, N., Vuaillat, C., Androdias, G. & Nataf, S. From bone marrow to microglia: barriers and avenues. Trends Immunol. 29, 227–234 (2008).

    CAS  PubMed  Google Scholar 

  29. 29.

    Lampron, A., Pimentel-coelho, P. M. & Rivest, S. Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration. J. Comp. Neurol. 521, 3863–3876 (2013).This study describes the migration of bone-marrow-derived cells through the BBB without the need for irradiation in a mouse model subjected to hypoxic–ischaemic brain injury.

    CAS  PubMed  Google Scholar 

  30. 30.

    International Union of Immunological Societies & World Health Organization. Chemokine / chemokine receptor nomenclature. J. Leukoc. Biol. 70, 465–466 (2001).

    Google Scholar 

  31. 31.

    Troletti, C. D., de Goede, P., Kamermans, A. & de Vries, H. E. Molecular alterations of the blood–brain barrier under inflammatory conditions: the role of endothelial to mesenchymal transition. Biochim. Biophys. Acta 1862, 452–460 (2016).

    Google Scholar 

  32. 32.

    Hu, P. et al. CNS inflammation and bone marrow neuropathy in type 1 diabetes. Am. J. Pathol. 183, 1608–1620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Li, Y., Alatan, G., Ge, Z. & Liu, D. Effects of benazepril on functional activity of endothelial progenitor cells from hypertension patients. Clin. Exp. Hypertens. 36, 545–549 (2014).

    CAS  PubMed  Google Scholar 

  34. 34.

    Biancardi, V. C. et al. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension 63, 572–579 (2014).

    CAS  PubMed  Google Scholar 

  35. 35.

    Zhang, M., Mao, Y., Ramirez, S. H., Tuma, R. F. & Chabrashvili, T. Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171, 852–858 (2010).

    CAS  PubMed  Google Scholar 

  36. 36.

    Zubcevic, J., Waki, H., Raizada, M. K. & Paton, J. F. R. Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension. Hypertension 57, 1026–1033 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Wu, C. Y. et al. Expression of angiotensin II and its receptors in activated microglia in experimentally induced cerebral ischemia in the adult rats. Mol. Cell. Biochem. 382, 47–58 (2013).

    CAS  PubMed  Google Scholar 

  38. 38.

    Liu, M., Shi, P. & Sumners, C. Direct anti-inflammatory effects of angiotensin-(1–7) on microglia. J. Neurochem. 136, 163–171 (2016).

    CAS  PubMed  Google Scholar 

  39. 39.

    Pocock, J. M. & Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 30, 527–535 (2007).

    CAS  PubMed  Google Scholar 

  40. 40.

    Santos-Carvalho, A., Aveleira, C. A., Elvas, F., Ambrósio, A. F. & Cavadas, C. Neuropeptide Y receptors Y1 and Y2 are present in neurons and glial cells in rat retinal cells in culture. Invest. Ophthalmol. Vis. Sci. 54, 429–443 (2013).

    CAS  PubMed  Google Scholar 

  41. 41.

    Jackson, L., Eldahshan, W., Fagan, S. C. & Ergul, A. Within the brain: the renin angiotensin system. Int. J. Mol. Sci. 19, E876 (2018).

    PubMed  Google Scholar 

  42. 42.

    Rodriguez-Pallares, J. et al. Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. Neurobiol. Dis. 31, 58–73 (2008).

    CAS  PubMed  Google Scholar 

  43. 43.

    Garrido-Gil, P., Valenzuela, R., Villar-Cheda, B., Lanciego, J. L. & Labandeira-Garcia, J. L. Expression of angiotensinogen and receptors for angiotensin and prorenin in the monkey and human substantia nigra: an intracellular renin-angiotensin system in the nigra. Brain Struct. Funct. 218, 373–388 (2013).

    CAS  PubMed  Google Scholar 

  44. 44.

    Garrido-Gil, P., Rodriguez-Perez, A. I., Fernandez-Rodriguez, P., Lanciego, J. L. & Labandeira-Garcia, J. L. Expression of angiotensinogen and receptors for angiotensin and prorenin in the rat and monkey striatal neurons and glial cells. Brain Struct. Funct. 222, 2559–2571 (2017).

    CAS  PubMed  Google Scholar 

  45. 45.

    Joglar, B. et al. The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. J. Neurochem. 109, 656–669 (2009).

    CAS  PubMed  Google Scholar 

  46. 46.

    van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Bedoui, S. et al. Relevance of neuropeptide Y for the neuroimmune crosstalk. J. Neuroimmunol. 134, 1–11 (2003).

    CAS  PubMed  Google Scholar 

  48. 48.

    Lackie, J. A Dictionary of Biomedicine (Oxford Univ. Press, 2010).

  49. 49.

    Banks, W. A., Kastin, A. J. & Broadwell, R. D. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2, 241–248 (1995).

    CAS  PubMed  Google Scholar 

  50. 50.

    Kastin, A. J. & Akerstrom, V. Nonsaturable entry of neuropeptide Y into brain. Am. J. Physiol. Endocrinol. Metab. 276, E479–E482 (1999).

    CAS  Google Scholar 

  51. 51.

    Chappa, A. K., Audus, K. L. & Lunte, S. M. Characteristics of substance P transport across the blood-brain barrier. Pharm. Res. 23, 1201–1208 (2006).

    CAS  PubMed  Google Scholar 

  52. 52.

    Dusi, V., Ghidoni, A., Ravera, A., De Ferrari, G. M. & Calvillo, L. Chemokines and heart disease: a network connecting cardiovascular biology to immune and autonomic nervous systems. Mediators Inflamm. 2016, 5902947 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Frangogiannis, N. G. et al. The microcirculation as a foundation of cardiovascular disease cytokines and the microcirculation in ischemia and reperfusion. J. Mol. Cell. Cardiol. 30, 2567–2576 (1998).

    CAS  PubMed  Google Scholar 

  54. 54.

    Correia, L. C. et al. Prognostic value of cytokines and chemokines in addition to the GRACE Score in non-ST-elevation acute coronary syndromes. Clin. Chim. Acta 411, 540–545 (2010).

    CAS  PubMed  Google Scholar 

  55. 55.

    Herring, N. Autonomic control of the heart: going beyond the classical neurotransmitters. Exp. Physiol. 100, 354–358 (2015).

    CAS  PubMed  Google Scholar 

  56. 56.

    Dehlin, H. M., Manteufel, E. J., Monroe, A. L., Reimer, M. H. & Levick, S. P. Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension. Int. J. Cardiol. 168, 4643–4651 (2013).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Capettini, L. S. et al. Role of renin-angiotensin system in inflammation, immunity and aging. Curr. Pharm. Des. 18, 963–970 (2012).

    CAS  PubMed  Google Scholar 

  58. 58.

    Harrison, D. G. et al. Inflammation, immunity, and hypertension. Hypertension 57, 132–140 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Schiffrin, E. The immune system: role in hypertension. Can. J. Cardiol. 29, 543–548 (2013).

    PubMed  Google Scholar 

  60. 60.

    Rodriguez-Iturbe, B., Pons, H., Quiroz, Y. & Johnson, R. J. The immunological basis of hypertension. Am. J. Hypertens. 27, 1327–1337 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Abais-Battad, J. M., Rudemiller, N. P. & Mattson, D. L. Hypertension and immunity: mechanisms of T cell activation and pathways of hypertension. Curr. Opin. Nephrol. Hypertens. 24, 470–474 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Rodriguez-Iturbe, B., Pons, H. & Johnson, R. J. Role of the immune system in hypertension. Physiol. Rev. 97, 1127–1164 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ganta, C. K. et al. Central angiotensin II-enhanced splenic cytokine gene expression is mediated by the sympathetic nervous system. Am. J. Physiol. Heart Circ. Physiol. 289, H1683–H1691 (2005).

    CAS  PubMed  Google Scholar 

  64. 64.

    Carnevale, D. et al. The angiogenic factor PIGF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. Immunity 41, 737–752 (2014).

    CAS  PubMed  Google Scholar 

  65. 65.

    Carnevale, D. et al. A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication. Nat. Commun. 7, 13035 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Calvillo, L. et al. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J. Cardiovasc. Pharmacol. 58, 500–507 (2011).

    CAS  PubMed  Google Scholar 

  67. 67.

    Harrison, D. G., Marvar, P. J. & Titze, J. M. Vascular inflammatory cells in hypertension. Front. Physiol. 3, 128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Dixon, K. B., Davies, S. S. & Kirabo, A. Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension. Am. J. Physiol. Heart Circ. Physiol. 312, H368–H374 (2017).

    PubMed  Google Scholar 

  69. 69.

    Caillon, A. et al. γδ T cells mediate angiotensin II-induced hypertension and vascular injury. Circulation 135, 2155–2162 (2017).

    CAS  PubMed  Google Scholar 

  70. 70.

    Madhur, M. S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).

    CAS  PubMed  Google Scholar 

  71. 71.

    Carnevale, D. & Lembo, G. Immunological aspects of hypertension. High Blood Press. Cardiovasc. Prev. 23, 91–95 (2016).

    CAS  PubMed  Google Scholar 

  72. 72.

    Harrison, D. G. The immune system in hypertension. Trans. Am. Clin. Clim. Assoc. 125, 130–140 (2014).

    Google Scholar 

  73. 73.

    Rosin, N. L., Sopel, M., Falkenham, A., Myers, T. L. & Legare, J.-F. Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis. Hypertens. Res. 35, 449–456 (2012).

    CAS  PubMed  Google Scholar 

  74. 74.

    Nguyen, H. et al. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc. Res. 97, 696–704 (2013).

    CAS  PubMed  Google Scholar 

  75. 75.

    Lee, D. L. et al. Angiotensin II hypertension is attenuated in interleukin-6 knockout mice. Am. J. Physiol. 290, H935–H940 (2006).

    CAS  Google Scholar 

  76. 76.

    Didion, S. P., Kinzenbaw, D. A., Schrader, L. I., Chu, Y. & Faraci, F. M. Endogenous interleukin-10 inhibits angiotensin II-induced vascular dysfunction. Hypertension 54, 619–624 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Luedike, P. et al. Circulating macrophage migration inhibitory factor (MIF) in patients with heart failure. Cytokine 110, 104–109 (2018).

    CAS  PubMed  Google Scholar 

  78. 78.

    Busche, S., Gallinat, S., Fleegal, M. A., Raizada, M. K. & Sumners, C. Novel role of macrophage migration inhibitory factor in angiotensin II regulation of neuromodulation in rat brain. Endocrinology 142, 4623–4630 (2001).

    CAS  PubMed  Google Scholar 

  79. 79.

    Barbosa, R. M. et al. Increased expression of macrophage migration inhibitory factor in the nucleus of the solitary tract attenuates renovascular hypertension in rats. Am. J. Hypertens. 30, 435–443 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Winklewski, P. J., Radkowski, M., Wszedybyl-Winklewska, M. & Demkow, U. Brain inflammation and hypertension: the chicken or the egg? J. Neuroinflamm. 12, 85 (2015).

    Google Scholar 

  81. 81.

    Han, C., Wu, W., Ale, A., Kim, M. S. & Cai, D. Central leptin and tumor necrosis factor-α (TNFα) in diurnal control of blood pressure and hypertension. J. Biol. Chem. 291, 15131–15142 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Venegas-Pont, M. et al. Tumor necrosis factor-alpha antagonist etanercept decreases blood pressure and protects the kidney in a mouse model of systemic lupus erythematosus. Hypertension 56, 643–649 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Crislip, G. R. & Sullivan, J. C. T cell involvement in sex differences in blood pressure control. Clin. Sci. 130, 773–783 (2016).

    CAS  PubMed  Google Scholar 

  84. 84.

    Goulopoulou, S., McCarthy, C. G. & Webb, R. C. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol. Rev. 68, 142–167 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Hernanz, R. et al. Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension. Br. J. Pharmacol. 172, 3159–3176 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Matsuda, S. et al. Angiotensin II activates MCP-1 and induces cardiac hypertrophy and dysfunction via toll-like receptor 4. J. Atheroscler. Thromb. 22, 833–844 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Kashyap, S. et al. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. Am. J. Physiol. Renal Physiol. 310, F372–F384 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Moll, N. M. & Ransohoff, R. M. CXCL12 and CXCR4 in bone marrow physiology. Expert Rev. Hematol. 3, 315–322 (2010).

    CAS  PubMed  Google Scholar 

  89. 89.

    Wei, S.-G., Zhang, Z.-H., Yu, Y., Weiss, R. M. & Felder, R. B. Central actions of the chemokine stromal cell-derived factor 1 contribute to neurohumoral excitation in heart failure rats. Hypertension 59, 991–998 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Alexandru, N., Popov, D., Dragan, E., Andrei, E. & Georgescu, A. Circulating endothelial progenitor cell and platelet microparticle impact on platelet activation in hypertension associated with hypercholesterolemia. PLOS ONE 8, e52058 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Liu, X. et al. Associations between polymorphisms of the CXCL12 and CNNM2 gene and hypertension risk: a case-control study. Gene 675, 185–190 (2018).

    CAS  PubMed  Google Scholar 

  92. 92.

    Mehta, N. N. et al. Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Eur. Heart J. 35, 2115–2122 (2014).

    CAS  PubMed  Google Scholar 

  93. 93.

    Klimczak-Tomaniak, D. et al. CXCL12 in patients with chronic kidney disease and healthy controls: relationships to ambulatory 24-hour blood pressure and echocardiographic measures. Cardiorenal Med. 8, 249–258 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Park, M. E. et al. Neuropeptide Y induces hematopoietic stem / progenitor cell mobilization by regulating matrix metalloproteinase-9 activity through Y1 receptor in osteoblasts. Stem Cells 34, 2145–2156 (2016).This work provides evidence that NPY-deficient mice have significantly impaired HSPC mobilization.

    CAS  PubMed  Google Scholar 

  95. 95.

    Zukowska-Grojec, Z. Neuropeptide Y. A novel sympathetic stress hormone and more. Ann. NY Acad. Sci. 771, 219–233 (1995).

    CAS  PubMed  Google Scholar 

  96. 96.

    Adrian, T. E. et al. Neuropeptide Y in the human male genital tract. Life Sci. 35, 2643–2648 (1984).

    CAS  PubMed  Google Scholar 

  97. 97.

    Tain, Y. L., Huang, L. T., Chan, J. Y. H. & Lee, C. T. Transcriptome analysis in rat kidneys: importance of genes involved in programmed hypertension. Int. J. Mol. Sci. 16, 4744–4758 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Cuculi, F. et al. Relationship of plasma neuropeptide Y with angiographic, electrocardiographic and coronary physiology indices of reperfusion during ST elevation myocardial infarction. Heart 99, 1198–1203 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Millar, B. C. et al. Positive and negative contractile of neuropeptide Y on ventricular effects cardiomyocytes. Am. J. Physiol. 261, H1727–H1733 (1991).

    CAS  PubMed  Google Scholar 

  100. 100.

    McDermott, B. J. & Bell, D. NPY and cardiac diseases. Curr. Top. Med. Chem. 7, 1692–1703 (2007).

    CAS  PubMed  Google Scholar 

  101. 101.

    Zhang, K. et al. Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses. J. Am. Coll. Cardiol. 60, 1678–1689 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Maisel, A. S. et al. Elevation of plasma neuropeptide Y levels in congestive heart failure. Am. J. Med. 86, 43–48 (1989).

    CAS  PubMed  Google Scholar 

  103. 103.

    Wang, Y. et al. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 298, H275–H2786 (2010).

    CAS  PubMed  Google Scholar 

  104. 104.

    Zhu, X., Gillespie, D. G. & Jackson, E. K. NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4. Am. J. Physiol. Heart Circ. Physiol. 309, H1528–H1542 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Schwarz, H., Villiger, P. M., von Kempis, J. & Lotz, M. Neuropeptide Y is an inducible gene in the human immune system. J. Neuroimmunol. 51, 53–61 (1994).

    CAS  PubMed  Google Scholar 

  106. 106.

    Farzi, A., Reichmann, F. & Holzer, P. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour. Acta Physiol. 213, 603–627 (2015).

    CAS  Google Scholar 

  107. 107.

    Rozengurt, E. Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists. J. Cell. Physiol. 177, 507–517 (1998).

    CAS  PubMed  Google Scholar 

  108. 108.

    Wheway, J., Herzog, H. & Mackay, F. NPY and receptors in immune and inflammatory diseases. Curr. Top. Med. Chem. 7, 1743–1752 (2007).

    CAS  PubMed  Google Scholar 

  109. 109.

    Dimitrijevic, M. & Stanojevic, S. The intriguing mission of neuropeptide Y in the immune system. Amino Acids 45, 41–53 (2013).

    CAS  PubMed  Google Scholar 

  110. 110.

    Hassani, H., Lucas, G., Rozell, B. & Ernfors, P. Attenuation of acute experimental colitis by preventing NPY Y1 receptor signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G550–G556 (2005).

    CAS  PubMed  Google Scholar 

  111. 111.

    Chandrasekharan, B., Nezami, B. G. & Srinivasan, S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G949–G957 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Ferreira, R. et al. Neuropeptide y modulation of interleukin-1β (IL-1β)-induced nitric oxide production in microglia. J. Biol. Chem. 285, 41921–41934 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Park, M. H., Min, W. K., Jin, H. K. & Bae, J. S. Role of neuropeptide Y in the bone marrow hematopoietic stem cell microenvironment. BMB Rep. 48, 645–646 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Singh, P. et al. Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells. J. Clin. Invest. 127, 4527–4540 (2017).This paper describes a role for NPY in regulating HSPC trafficking in response to cytokine treatment and identifies a CD26-mediated NPY axis.

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Kourtesis, I., Kasparov, S., Verkade, P. & Teschemacher, A. G. Ultrastructural correlates of enhanced norepinephrine and neuropeptide Y cotransmission in the spontaneously hypertensive rat brain. ASN Neuro 7, 1–19 (2015).

    CAS  Google Scholar 

  116. 116.

    Michalkiewicz, M., Knestaut, K. M., Bytchkova, E. Y. & Michalkiewicz, T. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension 41, 1056–1062 (2003).

    CAS  PubMed  Google Scholar 

  117. 117.

    Li, L., Jo, A., Abe, K. & Zukowska, Z. Chronic stress induces rapid occlusion of angioplasty-injured rat carotid artery by activating neuropeptide Y and its Y1 receptors. Arterioscler. Thromb. Vasc. Biol. 25, 2075–2080 (2005).

    CAS  PubMed  Google Scholar 

  118. 118.

    Harrison, S., Geppetti, P. & Substance, P. Int. J. Biochem. Cell Biol. 33, 555–576 (2001).

    CAS  PubMed  Google Scholar 

  119. 119.

    O’Connor, T. M. et al. The role of substance P in inflammatory disease. J. Cell. Physiol. 201, 167–180 (2004).

    PubMed  Google Scholar 

  120. 120.

    Maggi, C. A. Tachykinins and calcitonin gene-related peptide (CGRP) as co- transmitters released from peripheral endings of sensory nerves. Prog. Neurobiol. 45, 1–98 (1995).

    CAS  PubMed  Google Scholar 

  121. 121.

    Fiscus, R. R. et al. N omega-nitro-L-arginine blocks the second phase but not the first phase of the endothelium-dependent relaxations induced by substance P in isolated rings of pig carotid artery. J. Cardiovasc. Pharmacol. 20, S105–S108 (1992).

    CAS  PubMed  Google Scholar 

  122. 122.

    Meléndez, G. C., Manteufel, E. J., Dehlin, H. M., Register, T. C. & Levick, S. P. Non-human primate and rat cardiac fibroblasts show similar extracellular matrix-related and cellular adhesion gene responses to substance P. Heart Lung Circ. 24, 395–403 (2015).

    PubMed  Google Scholar 

  123. 123.

    Hancock, J. C. & Lindsay, G. W. Enhanced ganglionic responses to substance P in spontaneously hypertensive rats. Peptides 21, 535–541 (2000).

    CAS  PubMed  Google Scholar 

  124. 124.

    Levick, S. P., Murray, D. B., Janicki, J. S. & Brower, G. L. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension 55, 270–276 (2010).This paper provides evidence that substance P can stimulate ANGII production in cardiac inflammatory cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Hammer, A., Stegbauer, J. & Linker, R. A. Macrophages in neuroinflammation: role of the renin-angiotensin-system. Pflugers Arch. Eur. J. Physiol. 469, 431–444 (2017).This paper reviews the role of ANG-(1–7) as an anti-inflammatory and antihypertensive molecule.

    CAS  Google Scholar 

  126. 126.

    Santos, R. A. S. et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol. Rev. 98, 505–553 (2018).

    CAS  PubMed  Google Scholar 

  127. 127.

    Gironacci, M. M., Cerniello, F. M., Longo Carbajosa, N. A., Goldstein, J. & Cerrato, B. D. Protective axis of the renin-angiotensin system in the brain. Clin. Sci. 127, 295–306 (2014).

    CAS  PubMed  Google Scholar 

  128. 128.

    Mori, J. et al. Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity. Am. J. Physiol. Ren. Physiol. 306, F812–F821 (2014).

    CAS  Google Scholar 

  129. 129.

    Magalhaes, G. S. et al. Angiotensin-(1–7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation. Br. J. Pharmacol. 172, 2330–2342 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Yang, J. et al. Endogenous activated angiotensin-(1–7) plays a protective effect against atherosclerotic plaques unstability in high fat diet fed ApoE knockout mice. Int. J. Cardiol. 184, 645–652 (2015).

    PubMed  Google Scholar 

  131. 131.

    Patel, V. B., Basu, R. & Oudit, G. Y. ACE2/Ang 1–7 axis: A critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity. Adipocyte 5, 306–311 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Lu, W. et al. Angiotensin-(1–7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis. Braz. J. Med. Biol. Res. 50, e5594 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Rodrigues Prestes, T. R., Rocha, N. P., Miranda, A. S., Teixeira, A. L. & Simoes-E-Silva, A. C. The anti-inflammatory potential of ACE2/angiotensin-(1–7)/Mas receptor axis: evidence from basic and clinical research. Curr. Drug Targets 18, 1301–1313 (2017).

    CAS  PubMed  Google Scholar 

  134. 134.

    Goldstein, J. et al. Angiotensin-(1–7) protects from brain damage induced by shiga toxin 2-producing enterohemorrhagic Escherichia coli. Am. J. Physiol. Regul. Integr. Comp. Physiol. 311, R1173–R1185 (2016).

    Google Scholar 

  135. 135.

    Cuffee, Y., Ogedegbe, C., Williams, N. J., Ogedegbe, G. & Schoenthaler, A. Psychosocial risk factors for hypertension: an update of the literature. Curr. Hypertens. Rep. 16, 483 (2014).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Black, P. H. & Garbutt, L. D. Stress, inflammation and cardiovascular disease. J. Psychosom. Res. 52, 1–23 (2002).

    PubMed  Google Scholar 

  137. 137.

    Munakata, M. Clinical significance of stress-related increase in blood pressure: current evidence in office and out-of-office settings. Hypertens. Res. 41, 553–569 (2018).

    PubMed  Google Scholar 

  138. 138.

    Hänsel, A., Hong, S., Cámara, R. J. A. & von Känel, R. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci. Biobehav. Rev. 35, 115–121 (2010).

    PubMed  Google Scholar 

  139. 139.

    Rohleder, N. Stimulation of systemic low-grade inflammation by psychosocial stress. Psychosom. Med. 76, 181–189 (2014).

    PubMed  Google Scholar 

  140. 140.

    Mahmud, A. & Feely, J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension 46, 1118–1122 (2005).

    CAS  PubMed  Google Scholar 

  141. 141.

    Xu, T. Y., Zhang, Y., Li, Y., Zhu, D. L. & Gao, P. J. The association of serum inflammatory biomarkers with chronic kidney disease in hypertensive patients. Ren. Fail. 36, 666–672 (2014).

    CAS  PubMed  Google Scholar 

  142. 142.

    Karabacak, M., Yigit, M., Turkdogan, K. A. & Sert, M. The relationship between vascular inflammation and target organ damage in hypertensive crises. Am. J. Emerg. Med. 33, 497–500 (2015).

    PubMed  Google Scholar 

  143. 143.

    Fukutomi, M., Hoshide, S., Eguchi, K., Watanabe, T. & Kario, K. Low-grade inflammation and ambulatory blood pressure response to antihypertensive treatment: the ALPHABET study. Am. J. Hypertens. 26, 784–792 (2013).This study describes the link between immune factors and therapy outcomes in a randomized, open-label, multicentre trial on hypertension.

    CAS  PubMed  Google Scholar 

  144. 144.

    Poortvliet, R. K. E. et al. Biological correlates of blood pressure variability in elderly at high risk of cardiovascular disease. Am. J. Hypertens. 28, 469–479 (2015).

    CAS  PubMed  Google Scholar 

  145. 145.

    Edvinsson, L., Ekman, R. & Thulin, T. Increased plasma levels of neuropeptide Y-like immunoreactivity and catecholamines in severe hypertension remain after treatment to normotension in man. Regul. Pept. 32, 279–287 (1991).

    CAS  PubMed  Google Scholar 

  146. 146.

    Faulhaber, H. D. et al. Substance P in human essential hypertension. J. Cardiovasc. Pharmacol. 10, S172–S176 (1987).

    PubMed  Google Scholar 

  147. 147.

    Li, N.-F. et al. Higher levels of plasma TNF-alpha and neuropeptide Y in hypertensive patients with obstructive sleep apnea syndrome. Clin. Exp. Hypertens. 32, 54–60 (2010).

    PubMed  Google Scholar 

  148. 148.

    Yellowlees Douglas, J. et al. Bone marrow-CNS connections: implications in the pathogenesis of diabetic retinopathy. Prog. Retin. Eye Res. 31, 481–494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Tanira, M. O. & Al Balushi, K. A. Genetic variations related to hypertension: a review. J. Hum. Hypertens. 19, 7–19 (2005).

    CAS  PubMed  Google Scholar 

  150. 150.

    Saleh, M. A. et al. Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. J. Clin. Invest. 125, 1189–1202 (2015).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Devallière, J. & Charreau, B. The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. Biochem. Pharmacol. 82, 1391–1402 (2011).

    PubMed  Google Scholar 

  152. 152.

    Dale, B. L. & Madhur, M. S. Linking inflammation and hypertension via LNK/SH2B3. Curr. Opin. Nephrol. Hypertens. 25, 87–93 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Basson, J. J., De Las Fuentes, L. & Rao, D. C. Single nucleotide polymorphism-single nucleotide polymorphism interactions among inflammation genes in the genetic architecture of blood pressure in the framingham heart study. Am. J. Hypertens. 28, 248–255 (2015).

    CAS  PubMed  Google Scholar 

  154. 154.

    Padmanabhan, S. et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLOS Genet. 6, e1001177 (2010).

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    El-Achkar, T. M. et al. Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am. J. Physiol. Renal Physiol. 295, F534–F544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Warren, H. R. et al. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat. Genet. 49, 403–415 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Brady, R., Zaidi, S. I., Mayer, C. & Katz, D. M. BDNF is a target-derived survival factor for arterial baroreceptor and chemoafferent primary sensory neurons. J. Neurosci. 19, 2131–2142 (1999).

    CAS  PubMed  Google Scholar 

  158. 158.

    Wang, H. & Zhou, X. F. Injection of brain-derived neurotrophic factor in the rostral ventrolateral medulla increases arterial blood pressure in anaesthetized rats. Neuroscience 112, 967–975 (2002).

    CAS  PubMed  Google Scholar 

  159. 159.

    Golden, E. et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: Data from the baltimore longitudinal study of aging. PLOS ONE 5, e10099 (2010).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Takeia, N., Sasaoka, K., Higuchi, H., Endo, Y. & Hatanaka, H. BDNF increases the expression of neuropeptide Y mRNA and promotes differentiation/maturation of neuropeptide Y-positive cultured cortical neurons from embryonic and postnatal rats. Mol. Brain Res. 37, 283–289 (1996).

    Google Scholar 

  161. 161.

    Yoshimura, R., Ito, K. & Endo, Y. Differentiation/maturation of neuropeptide Y neurons in the corpus callosum is promoted by brain-derived neurotrophic factor in mouse brain slice cultures. Neurosci. Lett. 450, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  162. 162.

    Xapelli, S. et al. Interaction between neuropeptide Y (NPY) and brain-derived neurotrophic factor in NPY-mediated neuroprotection against excitotoxicity: a role for microglia. Eur. J. Neurosci. 27, 2089–2102 (2008).

    CAS  PubMed  Google Scholar 

  163. 163.

    Mattson, D. L. & Liang, M. Hypertension: from GWAS to functional genomics-based precision in hypertension. Nat. Rev. Nephrol. 13, 195–196 (2017).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Azam, A. B. & Azizan, E. A. B. Brief overview of a decade of genome-wide association studies on primary hypertension. Int. J. Endocrinol. 2018, 7259704 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Bartoloni, E., Alunno, A. & Gerli, R. Hypertension as a cardiovascular risk factor in autoimmune rheumatic diseases. Nat. Rev. Cardiol. 15, 33–44 (2018).

    PubMed  Google Scholar 

  166. 166.

    Wenze, U., Bode, M., Köhl, J. & Ehmke, H. A pathogenic role of complement in arterial hypertension and hypertensive end organ damage. Am. J. Physiol. Heart Circ. Physiol. 312, 349–354 (2017).

    Google Scholar 

  167. 167.

    Reddy, Y. N., Siedlecki, A. M. & Francis, J. M. Breaking down the complement system: a review and update on novel therapies. Curr. Opin. Nephrol. Hypertens. 26, 123–128 (2017).

    CAS  PubMed  Google Scholar 

  168. 168.

    Bossi, F., Bulla, R. & Tedesco, F. Endothelial cells are a target of both complement and kinin system. Int. Immunopharmacol. 8, 143–147 (2008).

    CAS  PubMed  Google Scholar 

  169. 169.

    Jeltsch-David, H. & Muller, S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat. Rev. Neurol. 10, 579–596 (2014).

    CAS  PubMed  Google Scholar 

  170. 170.

    McGlasson, S., Wiseman, S., Wardlaw, J., Dhaun, N. & Hunt, D. P. J. Neurological disease in lupus: toward a personalized medicine approach. Front. Immunol. 9, 1146 (2018).

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Meroni, P., Ronda, N., Raschi, E. & Borghi, M. O. Humoral autoimmunity against endothelium: theory or reality? Trends Immunol. 26, 275–281 (2005).

    CAS  PubMed  Google Scholar 

  172. 172.

    Anderson, C. L., Ganesan, L. P. & Robinson, J. M. The biology of the classical Fcγ receptors in non-hematopoietic cells. Immunol. Rev. 268, 236–240 (2015).

    PubMed  Google Scholar 

  173. 173.

    Norlander, A. E. & Madhur, M. S. Inflammatory cytokines regulate renal sodium transporters: how, where, and why? Physiol. Ren. Physiol. 313, F141–F144 (2017).

    CAS  Google Scholar 

  174. 174.

    Verhoeven, F., Prati, C., Maguin-Gaté, K., Wendling, D. & Demougeot, C. Glucocorticoids and endothelial function in inflammatory diseases: focus on rheumatoid arthritis. Arthritis Res. Ther. 18, 258 (2016).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Apostolopoulos, D. & Morand, E. F. It hasn’t gone away: the problem of glucocorticoid use in lupus remains. Rheumatology 56, i114–i122 (2017).

    CAS  PubMed  Google Scholar 

  176. 176.

    Schmidt, R. E., Grimbacher, B. & Witte, T. Autoimmunity and primary immunodeficiency: two sides of the same coin? Nat. Rev. Rheumatol. 14, 7–18 (2018).

    CAS  Google Scholar 

  177. 177.

    Sanidas, E. et al. Human immunodeficiency virus infection and hypertension. Is there a connection? Am. J. Hypertens. 31, 389–393 (2018).

    CAS  Google Scholar 

  178. 178.

    Shah, M. R. The broad spectrum of HIV-related cardiovascular disease. JACC Heart Fail. 3, 600–602 (2015).

    PubMed  Google Scholar 

  179. 179.

    Peterson, T. E. & Baker, J. V. Assessing inflammation and its role in comorbidities among persons living with HIV. Curr. Opin. Infect. Dis. 32, 8–15 (2019).

    CAS  PubMed  Google Scholar 

  180. 180.

    Li, G. H., Henderson, L. & Nath, A. Astrocytes as an HIV reservoir: mechanism of HIV infection. Curr. HIV Res. 14, 373–381 (2016).

    CAS  PubMed  Google Scholar 

  181. 181.

    Nath, A. Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J. Infect. Dis. 186, S193–S198 (2002).

    CAS  PubMed  Google Scholar 

  182. 182.

    Swirski, F. K. Inflammation and CVD in 2017: From clonal haematopoiesis to the CANTOS trial. Nat. Rev. Cardiol. 15, 79–80 (2018).

    PubMed  Google Scholar 

  183. 183.

    Ridker, P. M. et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391, 319–328 (2018).

    CAS  PubMed  Google Scholar 

  184. 184.

    Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  185. 185.

    Zhang, J. C. S. Role of T lymphocytes in hypertension. Curr. Opin. Pharmacol. 21, 14–19 (2015).

    PubMed  Google Scholar 

  186. 186.

    Tipton, A. J. & Baban, B. S. J. Female spontaneously hypertensive rats have a compensatory increase in renal regulatory T cells in response to elevations in blood pressure. Hypertension 64, 557–564 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Guzik, T. J. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Itani, H. A. et al. Activation of human T cells in hypertension: studies of humanized mice and hypertensive humans. Hypertension 68, 123–132 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Mattson, D. L. et al. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R407–R414 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Kim, S. et al. Hypertensive patients exhibit gut microbial dysbiosis and an increase in TH17 cells. J. Hypertens. 33, e77–e78 (2015).

    Google Scholar 

  191. 191.

    Meng, X. et al. Regulatory T cells in cardiovascular diseases. Nat. Rev. Cardiol. 13, 167–179 (2015).

    PubMed  Google Scholar 

  192. 192.

    Mian, M. O., Barhoumi, T., Briet, M. & Paradis, P. S. E. Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J. Hypertens. 34, 97–108 (2016).

    CAS  PubMed  Google Scholar 

  193. 193.

    Fabbiano, S. et al. Immunosuppression-independent role of regulatory T cells against hypertension-driven renal dysfunctions. Mol. Cell. Biol. 35, 3528–3546 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Dieterlen, M. T., John, K., Reichenspurner, H., Mohr, F. W. & Barten, M. J. Dendritic cells and their role in cardiovascular diseases: a view on human studies. J. Immunol. Res. 2016, 5946807 (2016).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Krishnan, S. M., Sobey, C. G., Latz, E., Mansell, A. & Drummond, G. R. IL-1b and IL-18: inflammatory markers or mediators of hypertension? Br. J. Pharmacol. 171, 5589–5602 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Harmon, A. et al. IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia. Hypertens. Pregnancy 34, 291–306 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful to J. Eugenio Ochoa (Department of Cardiovascular Neural and Metabolic Sciences, San Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy) for his valuable and constructive suggestions and to P. Wijnmaalen (IRCCS Istituto Auxologico Italiano, Milan, Italy) for help with creating the figures.

Author information

Affiliations

Authors

Contributions

L.C. researched the data for the article. All the authors discussed its content, wrote the manuscript and reviewed and edited it before submission. G.P. conceived the idea of the paper and coordinated the revisions.

Corresponding author

Correspondence to Gianfranco Parati.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

GWAS Catalog: https://www.ebi.ac.uk/gwas/

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Calvillo, L., Gironacci, M.M., Crotti, L. et al. Neuroimmune crosstalk in the pathophysiology of hypertension. Nat Rev Cardiol 16, 476–490 (2019). https://doi.org/10.1038/s41569-019-0178-1

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing