Signalling between the immune system and the central nervous system (CNS) through systemic routes, the vagus nerve, the hypothalamic–pituitary–adrenal (HPA) axis, the sympathetic nervous system (SNS) and the peripheral nervous system (PNS) are shown. Figure modified with permission from Molecular Psychiatry REF. 140 © (2005) Macmillan Magazines Ltd.

Glucocorticoids act on immune cells both directly and indirectly to suppress the induction of pro-inflammatory responses. They inhibit the production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumour-necrosis factor (TNF), while promoting the production of anti-inflammatory cytokines, such as IL-10, by macrophages and dendritic cells. They also promote apoptosis of macrophages, dendritic cells and T cells, leading to inhibition of immune responses. IFNγ, interferon-γ; NK cell, natural killer cell; T_C, cytotoxic T cell; T_H, T helper cell.

Glucocorticoids bind to glucocorticoid receptors in the cytosol, which displaces heat-shock protein 90 (HSP90) and allows receptor dimerization, movement into the nucleus and binding of the glucocorticoid–glucocorticoid-receptor complex to DNA. This leads to transcription and translation of proteins, including inhibitor of nuclear factor-κB (IκB). IκB then sequesters NF-κB, preventing it from activating transcription of pro-inflammatory cytokines. In addition, the glucocorticoid–glucocorticoid-receptor complex can interact with NF-κB directly to suppress cytokine production136. Noradrenaline binding to β-adrenergic receptors at the cell surface induces cyclic AMP (cAMP) and protein kinase A (PKA) activation, which inhibits cytokine production through inhibition of NF-κB. Acetylcholine binds to nicotinic cholinergic cell-surface receptors and inhibits cytokine production again through inhibition of NF-κB95. TLR, Toll-like receptor.

Neurotransmitters released through nerve terminals can both directly and indirectly affect immune responses. With the exception of vasoactive intestinal peptide (VIP), these neuropeptides stimulate the production of pro-inflammatory cytokines. In addition, some neuropeptides and their receptors are expressed by immune cells, including acetylcholine; VIP; calcitonin gene-related peptide (CGRP); substance P; muscarinic and nicotinic acetylcholine receptors; and serotonin receptors, such as 5HTT (5-hydroxytryptamine transporter), 5HT1A, 5HT2 and 5HT7. CRH, corticotropin-releasing hormone.