Bidirectional communication between the neuroendocrine system and the immune system: relevance to health and diseases

Srinivasan ThyagaRajan, Hannah P Priyanka, Srinivasan ThyagaRajan, Hannah P Priyanka

Abstract

In the past century, physiological, molecular, and cellular-based studies have proved that the functions of the nervous system, endocrine system, and immune system are dependent upon each other and that this interaction among these systems determines the maintenance of health or susceptibility to infections. The release of neurotransmitters and neuropeptides from the brain is a response to external environmental stimuli that influences the release of hormones from the pituitary in order to regulate the functions such as metabolism and growth, reproduction, etc. In addition, there are direct sympathetic noradrenergic and peptidergic innervations of primary (bone marrow and thymus) and secondary (spleen, lymph nodes, and lymphoid tissues) lymphoid organs. The neurotransmitters and neuropeptides released in these lymphoid organs then bind to specific receptors on the cells of the immune system to modulate their functions. Another circuit in this bidirectional communication involves the products of the immune system, for e.g., cytokines that can cross the blood-brain barrier to alter the activities of the neuronal function in the central nervous system especially during fever and inflammation in infectious diseases and cancer. Dysregulation of the interactions between the neuroendocrine and immune system due to alterations in the neural activity, secretion of hormones and cytokines, and synthesis of growth factors has been demonstrated to promote the pathogenesis and progression of infectious and autoimmune diseases, cancer, and neurodegenerative diseases. It is imperative that further research is carried out to understand the mechanisms of neuroendocrine-immune interactions to facilitate development of better treatment strategies for neurodegenerative diseases.

Keywords: Brain; Cytokine; Hormone; Lymphoid organs; Neurotransmitter.

Conflict of interest statement

Competing interests – None

Figures

Fig. 1:
Fig. 1:
Bidirectional communication between the neuroendocrine system and immune system.

  1. The bidirectional interaction is mainly through neurotransmitter-, hormonal-, and cytokine-specific pathways. The CNS influences the immune system via neuroendocrine outflow, and autonomic and sensory nerves that innervate lymphoid tissue. Peripherally, cytokines produced by the immune cells under the influence of neuronal activity cross the blood-brain barrier to influence CNS functions. There is a great complexity in neural-immune interactions.

  2. Neurotransmitter-specific and neuropeptidergic nerves are distributed in the rostral sections of the brain arising from the cell bodies located in the caudal portions of the brain. The neuroglial cells, astrocytes and microglia, regulate the neuronal survival through the release of cytokines and growth factors while the oligodendrocytes are critical to myelin formation. The neuroendocrine systems in the hypothalamus control metabolism and growth by influencing the release of hormones from the pituitary.

  3. Noradrenergic nerves originate from ganglia and are distributed to specific lymphoid compartments in lymphoid organs and the effects are mediated through the receptors for neurotransmitters on the cells of the immune system. The presence of β2-adrenergic receptors (AR) on the subpopulations of lymphoid cells facilitates the binding of norepinephrine (NE) to alter the release of cytokines, growth factors, and immune molecules that cross the blood-brain barrier to alter brain functions.

References

    1. Besedovsky HO, del Rey A. Physiological implications of the immuno-neuro-endocrine network. Psychoneuroimmunology. In: Ader R, Cohen N, Felten DL, editors. 2nd ed. New York: Academic Press; 1991. pp. 589–608.
    1. Dinarello CA. IL-1: discoveries, controversies and future directions. Eur J Immunol. 2010;40(3):599–606.
    1. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. 1995;2(4):241–248.
    1. Dunn A. Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism paralleling the increased plasma corticosterone. Life Science. 1988;43:429–435.
    1. Mohan Kumar PS, ThyagaRajan S, Quadri SK. Interleukin-1 stimulates the release of dopamine and dihydroxyphenylacetic acid from the hypothalamus in vivo. Life Science. 1991;48:925–930.
    1. Breder CD, Dinarello CA, Saper CB. Interleukin-1 immunoreactive innervation of the human hypothalamus. Science. 1988;240(4850):321–324.
    1. Spangelo BL, Gorospe WC. Role of the cytokines in the neuroendocrine-immune system axis. Front Neuroendocrinol. 1995;16(1):1–22.
    1. Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am. 2009;29(2):247–264.
    1. Thayer JF, Sternberg EM. Neural aspects of immunomodulation: focus on the vagus nerve. Brain Behav Immun. 2010;24(8):1223–1228.
    1. Ader R. Conditioned immunomodulation: Research needs and directions. Brain Behav Immun. 2003;17:S51–S57.
    1. Quan N, Herkenham M. Connecting cytokines and brain: a review of current issues. Histol Histopathol. 2002;17(1):273–288.
    1. Yong VW, Rivest S. Taking advantage of the systemic immune system to cure brain diseases. Neuron. 2009;64(1):55–60.
    1. Bernardes-Silva M, Anthony DC, Issekutz AC et al. Recruitment of neutrophils across the blood-brain barrier: the role of E- and P-selectins. J Cereb Blood Flow Metab. 2001;21(9):1115–1124.
    1. Del Maschio A, Zanetti A, Corada M et al. Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions. J Cell Biol. 1996;135(2):497–510.
    1. Denes A, Thornton P, Rothwell NJ et al. Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun. 2010;24(5):708–723.
    1. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16(11):1267–1276.
    1. Felten DL, Felten SY, Carlson SL et al. Noradrenergic and peptidergic innervation of lymphoid tissue. Journal of Immunology. 1985;135:755s–765s.
    1. Bellinger DL, Lorton D, Lubahn C . Innervation of lymphoid organs—Association of nerves with cells of the immune system and their implications in disease. Psychoneuroimmunology. In: Ader R, Felten DL, Cohen N, editors. Vol. 1. San Diego: Academic Press; 2001. pp. 5–111.
    1. Bellinger DL, Madden KS, Lorton D . Age-related alterations in neural-immune interactions and neural strategies in immunosenescence. Psychoneuroimmunology. In: Ader R, Felten DL, Cohen N, editors. Vol. 1. Vol. 2001. San Diego: Academic Press; pp. 241–288.
    1. Madden KS. Catecholamines, sympathetic innervation, and immunity. Brain Behav Immun. 2003;17(Suppl 1):S5–S10.
    1. Thyagarajan S, Felten DL. Modulation of neuroendocrine–immune signaling by Ldeprenyl and L-desmethyldeprenyl in aging and mammary cancer. Mechanisms of Ageing and Development. 2002;123:1065–1079.
    1. Tabarowski Z, Gibson-Berry K, Felten SY. Noradrenergic and peptidergic innervation of the mouse femur bone marrow, Acta Histochemica. 1996;98:453–457.
    1. Maestroni GJ, Conti A. Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells, Experimental Hematology. 1994;22:313–320.
    1. Yamazaki K, Allen TD. Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the ‘‘neuro-reticular complex.”. American Journal of Anatomy. 1990;187:261–276.
    1. Nance DM, Hopkins DA, Bieger D. Re-investigation of the innervation of the thymus gland in mice and rats. Brain Behav Immun. 1987;1:134–147.
    1. Singh U, Owen JJT. Studies on the maturation of thymus stem cells. The effects of catecholamines, histamine, and peptide hormones on the expression of T allo-antigens. European Journal of Immunology. 1976;6:59–62.
    1. Giron LTJ, Crutcher KA, Davis JN. Lymph nodes-a possible site for sympathetic neuronal regulation of immune responses. Annals of Neurology. 1980;8:520–525.
    1. Kin NW, Sanders VM. It takes nerve to tell T and B cells what to do. J Leukoc Biol. 2006;79(6):1093–1104.
    1. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun. 2007;21(6):736–745.
    1. Sanders VM. Epigenetic regulation of Th1 and Th2 cell development. Brain Behav Immun. 2006;20(4):317–324.
    1. Kouassi E, Li YS, Boukhris W et al. Opposite effects of the catecholamines dopamine and norepinephrine on murine polyclonal B-cell activation. Immunopharmacology. 1988;16:125–137.
    1. Kruszewska B, Felten SY, Moynihan JA. Alterations in cytokine and antibody production following chemical sympathectomy in two strains of mice. Journal of Immunology. 1995;155:4613–4620.
    1. Blalock JE. Shared ligands and receptors as a molecular mechanism for communication between the immune and neuroendocrine systems. Annals of New York Academcy of Sciences. 1994;741:292–298.
    1. Engler KL, Rudd ML, Ryan JJ et al. Autocrine actions of macrophage-derived catecholamines on interleukin-1 beta. J Neuroimmunol. 2005;160(1-2):87–91.
    1. Schulte-Herbru¨ggen O, Nassenstein C, Lommatzsch M et al. Tumor necrosis factor-a and interleukin-6 regulates secretion of brain-derived neurotrophic factor in human monocytes. J Neuroimmunol. 2005;160:204–209.
    1. Cole SW, Korin YD, Fahey JL et al. Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production. J Neuroimmunol. 1998;161:610–616.
    1. Haraguchi S, Good RA, James-Yarish M et al. Induction of intracellular cAMP by a synthetic retroviral circulation following envelope peptide: a possible mechanism of immunopathogenesis in retroviral infections, Proceedings of National Academy of Sciences USA. 1995;92:5568–5571.
    1. Kelley SP, Moynihan JA, Stevens SY et al. Sympathetic nerve destruction in spleen in murine AIDS. Brain Behav Immun. 2003;17(2):94–109.
    1. Kelley SP, Moynihan JA, Stevens SY et al. Chemical sympathectomy has no effect on the severity of murine AIDS: murine AIDS alone depletes norepinephrine levels in infected spleen. Brain Behav Immun. 2002;16(2):118–139.
    1. Wieseler-Frank J, Jekich BM, Mahoney JH et al. A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus. Brain Behav Immun. 2007;21(5):711–718.
    1. Kaul M, Lipton SA. Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res. 2006;4:307–318.
    1. Evans SR, Yeh TM, Sacktor N et al. Selegiline transdermal system (STS) for HIV-associated cognitive impairment: open-label report of ACTG 5090. HIV Clinical Trials. 2007;8:437–446.
    1. Schifitto G, Zhang J, Evans SR et al. A multicenter trial of selegiline transdermal system for HIV-associated cognitive impairment. Neurology. 2007;69:1314–1321.
    1. Sohrabji F, Lewis DK. Estrogen-BDNF interactions: implications for neurodegenerative diseases. Front Neuroendocrinol. 2006;27(4):404–414.
    1. Romeo HE, Colombo LL, Esquifino AI et al. Slower growth of tumours in sympathetically denervated murine skin. J Auton Nerv Syst. 1991;32(2):159–164.
    1. Brenner GJ, Felten SY, Felten DL et al. Sympathetic nervous system modulation of tumor metastases and host defense mechanisms. J Neuroimmunol. 1992;37(3):191–201.
    1. Ben-Eliyahu S, Page GG, Schleifer SJ. Stress, NK cells, and cancer: Still a promissory note. Brain Behav Immun. 2007;21(7):881–887.
    1. McEwen BS, Gianaros PJ. Central role of the brain in stress and adaptation: links to socioeconomic status, health, and disease. Ann N Y Acad Sci. 2010;1186:190–222.
    1. Kiecolt-Glaser JK, Gouin JP, Hantsoo L. Close relationships, inflammation, and health. Neurosci Biobehav Rev. 2010;35(1):33–38.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe