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

Ilia J. Elenkov, Ronald L. Wilder, George P. Chrousos, E. Vízi

Research output: Contribution to journalArticle

1508 Citations (Scopus)

Abstract

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 β2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-α, and interferon-γ 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-β. 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-α, 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 α2- and β2-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.

Original languageEnglish
Pages (from-to)595-638
Number of pages44
JournalPharmacological Reviews
Volume52
Issue number4
Publication statusPublished - 2000

Fingerprint

Sympathetic Nervous System
Catecholamines
Immune System
Norepinephrine
Cytokines
Chronic Fatigue Syndrome
Brain
Interleukin-12
Humoral Immunity
Epinephrine
Neurotransmitter Agents
Tumor Necrosis Factor-alpha
Type 4 Cyclic Nucleotide Phosphodiesterase
Lymphocytes
Mucosal Immunity
Th1 Cells
Hematopoiesis
Transforming Growth Factors
Antigen-Presenting Cells
Thymocytes

ASJC Scopus subject areas

  • Pharmacology

Cite this

The sympathetic nerve - An integrative interface between two supersystems : The brain and the immune system. / Elenkov, Ilia J.; Wilder, Ronald L.; Chrousos, George P.; Vízi, E.

In: Pharmacological Reviews, Vol. 52, No. 4, 2000, p. 595-638.

Research output: Contribution to journalArticle

Elenkov, Ilia J. ; Wilder, Ronald L. ; Chrousos, George P. ; Vízi, E. / The sympathetic nerve - An integrative interface between two supersystems : The brain and the immune system. In: Pharmacological Reviews. 2000 ; Vol. 52, No. 4. pp. 595-638.
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