Cited by 1,025Neuropeptides and Animal PhysiologyVagus Nerve Stimulation ResearchT-cell and B-cell Immunology

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Noradrenergic and peptidergic innervation of lymphoid tissue

Felten, D L, Felten, S Y, Carlson, S L, Olschowka, J A, Livnat, S·1985·The Journal of Immunology

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Abstract

Sympathetic noradrenergic nerve fibers innervate both the vasculature and parenchymal fields of lymphocytes and associated cells in several lymphoid organs, including the thymus, spleen, lymph nodes, gut-associated lymphoid tissue (GALT), and bone marrow, in a variety of mammalian species. This innervation is both regional and specific, and generally is directed into zones of T lymphocytes and plasma cells rather than into nodular regions or B lymphocyte regions. In the thymus, noradrenergic fibers enter with nerve bundles and plexuses around blood vessels, travel into the cortex from subcapsular plexuses and with the vasculature, and branch into the parenchyma of the thymic cortex. The vasculature and parenchymal regions of both the outer and deep cortex are innervated by these fibers. In the spleen, noradrenergic fibers enter with the vasculature, travel along the trabeculae and along the branching vasculature, and are distributed mainly in the white pulp along the central artery and associated periarterial lymphatic sheath. Fibers branch from a dense plexus around the central artery and travel into the parenchyma, where they end among fields of lymphocytes and other cell types. In lymph nodes, noradrenergic fibers enter at the hilus, travel along the vasculature and in a subcapsular plexus, and branch into the parenchyma in paracortical and cortical regions, where they end among lymphocytes. In the GALT, represented in these studies by rabbit appendix, sacculus rotundus, and Peyer’s patches, noradrenergic fibers enter at the serosal surface, travel longitudinally with the muscularis interna, turn radially into internodular plexuses, plunge directly through the thymus-dependent zones, and ramify profusely among lymphocytes, enterochromaffin cells, and plasma cells in the interdomal regions. In the bone marrow, noradrenergic fibers enter with blood vessels, distribute deeply into the marrow on those vessels, and branch sparsely into the substance of the marrow. Immunocytochemical observations revealed the presence of neuro-peptide-like immuno-reactivity in the thymus and spleen. Vasoactive intestinal peptide (VIP)-like immunoreactivity is found in varicose profiles in the thymus within the cortex. In the spleen, immunoreactive profiles showing neuropeptide Y-like, Met-enkephalin-like, cholecystokinin-8 (CCK)-like, and neurotensin-like immunoreactivity are present along the central artery of the white pulp and its smaller branches, with only sparse fibers of most of these peptides entering the parenchyma. CCK-like profiles are present in abundance in the white pulp among parenchymal elements. The presence of noradrenergic innervation and possible peptidergic innervation of a variety of lymphoid tissues suggests that these nerves may serve as an important link between the nervous system and elements of the immune system. Neural modulation of immune responses could utilize a number of possible mechanisms to influence the function of individual cells. Resolution of these mechanisms will require both in vitro testing of individual transmitters or modulators singly and in combination, and in vivo studies that take into account the local microenvironment and temporal influences of hormones and transmitters on specific cell types.

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Skobowiat, C., Postlethwaite, A. E., & Slominski, A. T. (2016) · Photochemistry and Photobiology · doi:10.1111/php.12642 · Cited by 82
“cord and brain with direct neurotransmission to the spleen through the sympathetic system (56).”
Background
Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity
Brinkman, D. J., ten Hove, A. S., Vervoordeldonk, M. J., Luyer, M. D. P., & de Jonge, W. J. (2019) · Cells · doi:10.3390/cells8070670 · Cited by 85
“possible synaptic-like connection with leukocytes [12,66].”
Without nerves, immunology remains incomplete –in vivo veritas
Shepherd, A. J., Downing, J. R., & Miyan, J. A. (2005) · Immunology · doi:10.1111/j.1365-2567.2005.02223.x · Cited by 83
Transcriptional Mechanisms for Induction of 5-HT1AReceptor mRNA and Protein in Activated B and T Lymphocytes
Abdouh, M., Storring, J. M., Riad, M., Paquette, Y., Albert, P. R., Drobetsky, E. A., & Kouassi, É. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m004559200 · Cited by 86
Cholinergic receptors of lymphocytes
Maśliński, W. (1989) · Brain Behavior and Immunity · doi:10.1016/0889-1591(89)90001-9 · Cited by 83
The bidirectional interaction between the sympathetic nervous system and immune mechanisms in the pathogenesis of hypertension
Carnagarin, R., Matthews, V. B., Zaldivia, M. T. K., Peter, K., & Schlaich, M. P. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14481 · Cited by 85
“Sympathetic nerves densely innervate the BM and upon activation can release progenitor cells seeding to the spleen with a subsequent increase in monocyte production (Felten et al., 1984; Felten et al., 1985; Dutta et al., 2012).”
Background
Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production through different molecular mechanisms in T cells activated via the T cell receptor/CD3 complex
Sun, L., & Ganea, D. (1993) · Journal of Neuroimmunology · doi:10.1016/0165-5728(93)90059-8 · Cited by 82
Consequences of spinal cord injury on the sympathetic nervous system
Wulf, M. J., & Tom, V. J. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.999253 · Cited by 90
“They project out of the spinal cord via the greater splanchnic nerve to the celiac ganglion, where the SPNs form synapses on the postganglionic neurons that then directly innervate the spleen (Felten et al., 1985; Straub, 2004; Nance and Sanders, 2007; Bratton et al., 2012).”
Background
Immunological Aetiology of Major Psychiatric Disorders
Sperner‐Unterweger, B. (2005) · Drugs · doi:10.2165/00003495-200565110-00004 · Cited by 83
Immunophysiology of Intestinal Electrolyte Transport
Powell, D. W. (1991) · Comprehensive physiology · doi:10.1002/cphy.cp060425 · Cited by 80
Substance P gene expression is regulated by interleukin‐1 in cultured sympathetic ganglia
Hart, R. P., Shadiack, A. M., & Jonakait, G. M. (1991) · Journal of Neuroscience Research · doi:10.1002/jnr.490290303 · Cited by 80
“Moreover, SP is one of the neuropeptides contained in fibers innervating the spleen, thymus, and lymph nodes (Felten et al., 1985; Fink and Weihe, 1988; Weihe et al., 1989; Popper et al., 1988; Bellinger et al., 1990; Kurkowski et al., 1990) and contacting mast cells in the intestine (Bienenstock et al.”
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Bidirectional communication between the neuroendocrine system and the immune system: relevance to health and diseases
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Interaction of neurotransmitters and neurochemicals with lymphocytes
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The central nervous system and inflammation in hypertension
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“For example, T cell rich organs such as the spleen and lymph nodes are highly innervated with sympathetic nerves [40,41].”
Background
VIP modulation of immune cell functions
la Fuente, M. D., Delgado, M., & Gomariz, R. P. (1996) · Advances in Neuroimmunology · doi:10.1016/s0960-5428(96)00002-2 · Cited by 78
Peptidergic innervation of rat lymphoid tissue and lung: Relation to mast cells and sensitivity to capsaicin and immunization
Nilsson, G. P., Alving, K., Ahlstedt, S., et al. (1990) · Cell and Tissue Research · doi:10.1007/bf00327753 · Cited by 78
“The presence of a noradrenergic and peptidergic innervation in a variety of lymphoid tissues suggests that these nerves may serve as an important link between the nervous system and the immune system (Felten et al. 1985; Lundberg et al. 1985b).”
Background
Topical Treatment of Ulcerative Proctitis with Lidocaine
Björck, S., Dahlström, A. B., & Ahlman, H. K. (1989) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365528909089256 · Cited by 78
Neural regulation of gastrointestinal inflammation: Role of the sympathetic nervous system
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“The greatest innervation density is found in areas of T lymphocyte aggregation (Felten et al., 1985; Kulkarni-Narla et al., 1999).”
Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: A systematic review across species
Walsh, C. P., Bovbjerg, D. H., & Marsland, A. L. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.013 · Cited by 87
The psychobiological links between chronic stress‐related diseases, periodontal/peri‐implant diseases, and wound healing
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Spread of Classic BSE Prions from the Gut via the Peripheral Nervous System to the Brain
Kaatz, M., Fast, C., Ziegler, U., Balkema‐Buschmann, A., Hammerschmidt, B., Keller, M., Oelschlegel, A. M., McIntyre, L., & Groschup, M. H. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.05.001 · Cited by 81
Differential regulation of neurotrophin expression by mitogens and neurotransmitters in mouse lymphocytes
Bentov, R. B., Appel, E., Kazimirsky, G., Braun, A. C., Renz, H. E., & Brodie, C. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00233-7 · Cited by 78
“Felten et al., 1985 .”
Noradrenergic sympathetic innervation of the spleen: IV. Morphometric analysis in adult and aged F344 rats
Bellinger, D. L., Felten, S. Y., Collier, T. J., & Felten, D. L. (1987) · Journal of Neuroscience Research · doi:10.1002/jnr.490180110 · Cited by 77
Self-citation
The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease
Giovangiulio, M. D., Verheijden, S., Bosmans, G., Stakenborg, N., Boeckxstaens, G. E., & Matteoli, G. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00590 · Cited by 81
“In detail, lamina propria antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages (MFs), are “educated” by intestinal bioactive factors, such as transforming growth factor-beta (TGF-β), retinoic acid, thymic stromal lymphopoietin, and mucins (1–5), to suppress inflammation and promote immunologi…”
Background

Authors: Felten, D. L., Felten, S. Y., Carlson, S. L., Olschowka, J. A., & Livnat, S.
Affiliations: University of Rochester Medicine (US)
ORCID: Carlson, S L
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 1985-08-01
Volume: 135
Issue: 2
Pages: 755-765
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.135.2.755
OpenAlex: W79466244
Cited by: 1,025
References: 0
Citations by year: 2026: 15 · 2025: 13 · 2024: 15 · 2023: 17 · 2022: 23 · 2021: 23 · 2020: 13 · 2019: 21 · 2018: 26 · 2017: 12 · 2016: 23 · 2015: 16 · 2014: 22 · 2013: 20 · 2012: 24
FWCI: 12.00
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: noradrenergic innervation, sympathetic nerve fibers, lymphoid tissue, thymus, spleen, lymph nodes, gut-associated lymphoid tissue, bone marrow, vasoactive intestinal peptide, neuropeptide Y, substance P, neurokinin-1 receptor, neurokinin-2 receptor, neurokinin-3 receptor, neurotensin, substance P antagonist
MeSH terms: Adrenergic Fibers, Animals, Appendix, Bone Marrow, Intestines, Lymph Nodes, Lymphocytes, Lymphoid Tissue, Nerve Tissue Proteins, Norepinephrine, Rabbits, Spleen, Thymus Gland, Neurotransmitter Agents, Mice, Rats

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Noradrenergic and peptidergic innervation of lymphoid tissue

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