Table 1.
Mediators of neuroimmunomodulation
| Name | Source(s) | Targets, functions, effects | Refs |
|---|---|---|---|
| Substance P | Central nervous system, peptidergic nerve fibres (c-fibres), macrophages, granulocytes, lymphocytes | Released antidromically as part of nociception. Increases lymphocyte output from lymph nodes, stimulates lymphocyte proliferation, causes mast cell degranulation. Blocks T-cell adhesion to fibronectin and can augment cytokine secretion from antigen-exposed cells in vitro. Neurokinin receptors present on endothelia, smooth muscle, lymphocytes, Langerhans' cells, mast cells. Neurokinin receptor activation causes rises in intracellular Ca2+. Related peptides neurokinin A and B are also released by c-fibres. | 24,63,64,68, 69,164–168 |
| Calcitonin gene-related peptide (CGRP) | c-fibres, lymphocytes | Induces vasodilation, plasma extravasation, mast cell degranulation. Inhibits antigen presentation by Langerhans' cells. Alters T-cell cytokine secretion and adhesion to fibronectin. CGRP receptor present on T-cell surface. Stimulation of CGRP receptors on Langerhans' cells brings about signalling through adenylate cyclase and cAMP. | 16,100–102,169 |
| Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) | Produced at nerve terminals in the CNS and PNS, as well as in lymphoid organs | Suppresses the induction of contact hypersensitivity. Inhibits Langerhans' cells antigen presentation in vitro. Down-regulates expression of macrophage costimulatory molecules. Released by sensory nerves upon damage/inflammation. Receptors present on cutaneous nerves, macrophages, Langerhans' cells and T cells. Receptor activation induces cAMP formation in Langerhans' cells. | 77,170,171 |
| Neuropeptide Y | Nerve terminals in the CNS and PNS, lymphoid organs, lymphocytes and monocytes | Suppresses natural killer cell activity. Co-released with norepinephrine from sympathetic terminals following depolarization, participating in neurogenic inflammation. NPY receptors expressed by dorsal root ganglion neurones. | 172–175 |
| Somatostatin | Nerve terminals in the CNS and PNS, lymphoid organs | Specific somatostatin receptors present on lymphocyte surface, Langerhans' cells. Along with CGRP and NPY, directly induces T-cell adhesion to fibronectin. Also directly stimulates T-cell cytokine secretion. Can enhance or reduce lymphocyte proliferation. | 112,124,176–178 |
| GnRH-I, -II (gonadotrophin- releasing hormone) | Neuronal cells, T lymphocytes | Increases surface expression and transcription of a laminin receptor in T cells. Laminin receptor thought to be important in facilitating T-cell extravasation and holding of memory T lymphocytes in areas of challenge. Also induces chemotaxis towards SDF-1/CXCL12. | 179 |
| α-melanocyte stimulating hormone (α-MSH) | Keratinocytes, Langerhans' cells, melanocytes | Synthesis by keratinocytes up-regulated by immunological challenge. May induce hapten-specific tolerance by modulating levels of interleukin-10. Decreases endothelial cell adherence, dendritic costimulatory molecule expression, antagonizes interleukin-1 activity. Melanocortin receptors expressed throughout the skin. POMC peptides stimulate melanogenesis. | 126,180–187 |
| Corticotropin-releasing hormone (CRH) and urocortin | Throughout the skin, may be transported to the skin via sensory nerves in rodents. Lymphocytes | Keratinocytes, mast cells, endothelia all carry CRH receptors. Can prompt mast cell degranulation, despite antinflammatory and antiproliferative properties. Stimulates POMC activity in cutaneous fibroblasts. | 125–128,130,131 |
| Adrenocorticotrophic hormone (ACTH) | Anterior pituitary, skin cells, leucocytes | Derived from POMC. Cells throughout the skin express melanocortin receptors responsive to ACTH and MSH. Induces expression of preprotachykinin and neurokinin receptor. POMC peptides stimulate melanogenesis. | 126,187–189 |
| Nerve growth factor (NGF) | Mast cells, fibroblasts and other cell types at sites of injury/inflammation | Binds TrkA receptors on sensory afferents. Essential for nerve fibre growth/development/ maintenance. Can influence mast cell activity. | 126 |
| Serotonin (5-HT) | Afferent nociceptors, mast cells (rodents only). Stored by lymphocytes and platelets | Enhances plasma extravasation induced by capsaicin. Proinflammatory, vasodilator. Noradrenergic termini in lymphoid organs may take up 5-HT for later release. Immune cells, keratinocytes, unmyelinated axons all thought to express HT receptors. | 86,190 |
| Endorphins and enkephalins | Langerhans' cells, mononuclear leucocytes, keratinocytes | Antinociceptive properties. Production stimulated by proinflammatory stimuli (e.g. TNF-α). Enhances mononuclear cell chemotaxis and interleukin-2 production. Opioid receptors present on keratinocytes. | 191–195 |
| Epinephrine and norepinephrine | Lymphocytes, macrophages, sympathetic neurones, keratinocytes, adrenal medulla (under acute stress) | Norepinephrine co-localizes with neuropeptide Y in lymphoid organs. Intradermal injection can suppress the sensitization and elicitation phases of contact sensitivity. Decreases proinflammatory cytokine expression, promote anti-inflammatory cytokine production. Can be an activator of the immune response; depends on the type of recipient cell and its activational and maturational state. Stimulation with physiological concentrations of catecholamines stimulates adenylate cyclase activity and cyclic AMP production. Keratinocytes, almost all leucocytes, including Langerhans' cells and mast cells, express adrenoreceptors. Α2-agonists inhibit interleukin-12 secretion by dendritic cells and therefore T helper 1 cell development. This inhibition is mediated through increases in intracellular cyclic AMP concentration. | 196–198 |
| Histamine | Mast cell granules, basophils. Platelets, dendritic cells and T cells produce histamine de novo | Potent vasodilator. Activates submucosal neurones. Increasesinterleukin-10 secretion, inhibits interleukin-12 secretion by dendritic cells and T helper 1 cell development as a result. This inhibition is mediated through increases in intracellular cAMP. Increased levels of CD80, CD86 and MHC class II on dendritic cells. Histamine receptors: expressors include neurones, endothelia, dendritic cells, T and B cells. T helper 1 cells predominantly express H1R. H2R is primarily coupled to adenylate cyclase – also capable of signalling through PLC. T helper 2 cells predominantly express H2R. | 199–202 |
| Acetylcholine | Cholinergic innervation, keratinocytes | Cholinergic receptors present on keratinocytes and lymphocytes. Induces norepinephrine secretion from lymphocytes. Depresses TNF-α secretion without affecting interleukin-10 levels. | 80,81,203,204 |
| Melatonin | Nervous system, immune system | Mammalian skin produces melatonin from serotonin. Melatonin receptors expressed in mammalian skin. Modulates lymphocyte proliferation and the T helper 1/T helper 2 cytokine balance. | 190,205,206 |
| ATP and ADP | Keratinocytes, nociceptors (in response to noxious stimuli) | Nucleotide (P2X/Y) receptors present on sensory nerve fibres – ATP responsive? ATP may exert an inhibitory effect on dendritic cell migration, prolonging exposure to antigen. | 207 |
| Potassium | Nervous system and other tissues (in response to noxious stimuli) | Activates T-cell adhesion to fibronectin, facilitating migration. Brings about β1-inegrin adhesion in the same way as ‘neuropeptides’; T-cell membrane depolarization and opening of the T-cell Kv1.3 voltage-gated K+ channel. | 208,209 |
CGRP, calcitonin gene-related peptide; CNS, central nervous system; NPY, neuropeptide y; POMC, pro-opiomelanocortin; PNS, peripheral nervous system; PLC, phospholipase C; SDF-1, stromal cell derived factor-1; TNF-α, tumour necrosis factor-α.