Brain inflammation and hypertension: the chicken or the egg?

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Abstract

Inflammation of forebrain and hindbrain nuclei controlling the sympathetic nervous system (SNS) outflow from the brain to the periphery represents an emerging concept of the pathogenesis of neurogenic hypertension. Angiotensin II (Ang-II) and prorenin were shown to increase production of reactive oxygen species and pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)) while simultaneously decreasing production of interleukin-10 (IL-10) in the paraventricular nucleus of the hypothalamus and the rostral ventral lateral medulla. Peripheral chronic inflammation and Ang-II activity seem to share a common central mechanism contributing to an increase in sympathetic neurogenic vasomotor tone and entailing neurogenic hypertension. Both hypertension and obesity facilitate the penetration of peripheral immune cells in the brain parenchyma. We suggest that renin-angiotensin-driven hypertension encompasses feedback and feedforward mechanisms in the development of neurogenic hypertension while low-intensity, chronic peripheral inflammation of any origin may serve as a model of a feedforward mechanism in this condition.

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Most cited references 67

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Global burden of hypertension: analysis of worldwide data

P. Kearney, M Whelton, K. Reynolds … (2005)

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The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.

I J Elenkov, R L Wilder, G P Chrousos … (2000)

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

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Autonomic innervation and regulation of the immune system (1987-2007).

Dwight Nance, Virginia Sanders (2007)

Since 1987, only a few neuroanatomical studies have been conducted to identify the origin of innervation for the immune system. These studies demonstrated that all primary and secondary immune organs receive a substantial sympathetic innervation from sympathetic postganglionic neurons. Neither the thymus nor spleen receive any sensory neural innervation; however, there is evidence that lymph nodes and bone marrow may be innervated by sensory neurons located in dorsal root ganglia. There is no neuroanatomical evidence for a parasympathetic or vagal nerve supply to any immune organ. Thus, the primary pathway for the neural regulation of immune function is provided by the sympathetic nervous system (SNS) and its main neurotransmitter, norepinephrine (NE). Activation of the SNS primarily inhibits the activity of cells associated with the innate immune system, while it either enhances or inhibits the activity of cells associated with the acquired/adaptive immune system. Innate immune cells express both alpha and beta-adrenergic receptor subtypes, while T and B lymphocytes express adrenergic receptors of the beta2 subtype exclusively, except for murine Th2 cells that lack expression of any subtype. Via these adrenergic receptors, NE is able to regulate the level of immune cell activity by initiating a change in the level of cellular activity, which often involves a change in the level of gene expression for cytokines and antibodies.

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Contributors

Pawel J Winklewski:

ORCID: http://orcid.org/0000-0002-1671-2163

pawelwinklewski@wp.pl

Marek Radkowski: marek.radkowski@wum.edu.pl

Magdalena Wszedybyl-Winklewska: magdalenawinklewska@gumed.edu.pl

Urszula Demkow: urszula.demkow@litewska.edu.pl

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 3 May 2015

Publication date PMC-release: 3 May 2015

Publication date Collection: 2015

Volume: 12

Electronic Location Identifier: 85

Affiliations

[ ]Institute of Human Physiology, Medical University of Gdansk, Tuwima Str. 15, 80-210 Gdansk, Poland

[ ]Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawinskiego Str. 3c, 02-106 Warsaw, Poland

[ ]Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Marszalkowska Str. 24, 00-576 Warsaw, Poland

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Pawel J Winklewski http://orcid.org/0000-0002-1671-2163

Article

Publisher ID: 306

DOI: 10.1186/s12974-015-0306-8

PMC ID: 4432955

PubMed ID: 25935397

SO-VID: b037f912-e8f4-4df5-b92f-1e35c2024b2a

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 February 2015

Date accepted : 23 April 2015

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ScienceOpen disciplines: Neurosciences

Keywords: brain inflammation,neurogenic hypertension,angiotensin ii,prorenin,reactive oxygen species,chronic inflammation,obesity

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ScienceOpen disciplines: Neurosciences

Keywords: brain inflammation, neurogenic hypertension, angiotensin ii, prorenin, reactive oxygen species, chronic inflammation, obesity

Brain inflammation and hypertension: the chicken or the egg?

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Neuronal Signaling

Most cited references 67

Global burden of hypertension: analysis of worldwide data

The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.

Autonomic innervation and regulation of the immune system (1987-2007).

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