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  • Review Article
  • Published:

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens

Nature Reviews Immunology volume 6, pages 318–328 (2006)Cite this article

Key Points

  • Local inflammation includes elements — pain and vasodilation — that are neurally mediated.

  • The systemic acute-phase response includes neurally mediated elements — fever and activation of the central hormonal stress response — that are mediated by the effects of immune factors on the hypothalamus.

  • The cellular and molecular components of the innate immune system provide the first line of defence against invading pathogens, through recognition of pathogen-associated molecular patterns (PAMPs) and initial nonspecific cellular and humoral responses. Immune mediators and cytokines that are subsequently released by the innate immune system rapidly activate nonspecific neural responses that both amplify local immune responses to clear pathogens and trigger systemic neuroendocrine and regional neural responses that eventually return the system to a resting state.

  • These neural responses include systemic hormonal responses (through the hypothalamic–pituitary–adrenal axis); regional neuronal responses (through the sympathetic and parasympathetic nervous systems) that innervate immune organs; and local neuronal responses (through the peripheral nervous system).

  • Immune cells contain the molecular machinery to respond to neural signals, including receptors and signalling pathways. Neurotransmitters (including noradrenaline and acetylcholine), neuropeptides (including opioids, substance P, neuropeptide Y and calcitonin gene-related peptide and hormones (glucocorticoids) alter innate immune-cell function through these molecular mechanisms.

  • The nervous system and innate immune system form a cohesive and integrated early host response to pathogens.

  • This interplay constitutes an important feedback loop that optimizes innate inflammatory responses to invading pathogens. Prolonged or inappropriate central nervous system counter-regulatory responses could predispose the host to excess inflammation (in the context of inadequate hormonal suppression) or uncontrolled infection (in the context of excess or prolonged anti-inflammatory hormonal responses).

Abstract

The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

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Figure 1: Schematic illustration of connections between the nervous and immune systems.
Figure 2: Effects of glucocorticoids on immune-cell populations.
Figure 3: Molecular mechanisms of neurotransmitter and glucocorticoid regulation of cytokine production.
Figure 4: Effects of the peripheral nervous system on immune-cell populations in lymphoid organs.

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Acknowledgements

The author would like to thank H. Gorby and C. Butts for their important contributions to this manuscript.

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  1. Section on Neuroendocrine Immunology and Behaviour, National Institute of Mental Health, National Institutes of Health, 5625 Fishers Lane, Room 4N-13, MSC-9401, Rockville, 20852, Maryland, USA

    Esther M. Sternberg

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Glossary

G-protein-coupled receptors

Cell-surface receptors that are coupled to G-proteins, and have seven transmembrane-spanning domains. The acetylcholine, adrenergic and neuropeptide receptors are all members of this family. Typically, activation of the G-protein-coupled receptor produces a diffusible second messenger that, in turn, triggers various biochemical cascades.

Sympathetic nervous system

(SNS). A division of the autonomic nervous system that consists of fibres projecting from the central nervous system, through ganglia near the spinal cord, to innervate organs such as the heart, lungs, intestine, blood vessels and sweat glands. In general, sympathetic nerves dilate the pupils, constrict peripheral blood vessels and increase heart rate.

Parasympathetic nervous system

A division of the autonomic nervous system that consists of nerve fibres projecting from the central nervous system and sacral portion of the spinal cord, which extend to nerve-cell clusters (ganglia) at specific sites, from which fibres are distributed to blood vessels, glands and other internal organs. Functions of parasympathetic nerves include slowing the heart rate; inducing the secretion of bile, insulin and digestive juices; dilating peripheral blood vessels; and contracting the bronchioles, pupils and oesophagus.

Delayed-type hypersensitivity

A cellular immune response to antigen that develops over 24–72 hours with the infiltration of T cells and monocytes, and depends on the production of T helper 1-cell-specific cytokines.

Noradrenaline

The primary neurotransmitter of the sympathetic nervous system. It is a biogenic amine derived from tyrosine and its metabolite dopamine, which is converted to noradrenaline by the enzyme β-hydroxylase.

Adrenaline

A neurotransmitter of the sympathetic nervous system. It is a biogenic amine derived from tyrosine and its metabolite dopamine, which is converted to adrenaline from noradrenaline by the enzyme phenylethanolamine-N-methyl transferase.

Vagus nerve

The main nerve trunk of the parasympathetic nervous system. It contains both afferent fibres that carry signals from the periphery to the brain, and efferent fibres that carry signals from the brain to the peripheral organs that it innervates.

Pro-opiomelanocortin

(POMC). A 241-amino-acid precursor polypeptide that is synthesized in corticotrophin cells of the pituitary gland. Biologically active peptides derived from POMC include adrenocorticotropic hormone, enkephalins and α-melanocyte-stimulating hormone.

Arcuate nucleus

A collection of neurons in the hypothalamus. It regulates the secretion of hormones through afferent dopaminergic projections to the pituitary.

Paraventricular nucleus

(PVN). A collection of neurons in the hypothalamus that are adjacent to the third ventricle. It contains mainly neurosecretory neurons that secrete corticotrophin-releasing hormone, which stimulates pituitary corticotrophs. In addition, PVN neurons project to the sympathetic brainstem nuclei, parasympathetic brainstem pre-ganglionic neurons and spinal cord.

Endorphins

Endogenous opioid peptides that are produced by the pituitary gland and the hypothalamus. They regulate feelings of pain and hunger.

Enkephalins

Short five-amino-acid polypeptides that are members of endogenous opioid family and that bind to opiate receptors.

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Sternberg, E. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6, 318–328 (2006). https://doi.org/10.1038/nri1810

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