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Reflex control of immunity

Key Points

  • During sterile injury or infection, the innate immune system produces cytokines as part of the innate immune response.

  • Molecules such as the cytokines tumour necrosis factor and interleukin-1 as well as high-mobility group box 1 protein are inherently toxic and can directly mediate the development of fever, shock, tissue injury, organ failure and even death.

  • Visceral reflexes provide physiological homeostasis to complex organ systems (for example, the baroreflex in the cardiovascular system), and these principles also operate in the control of innate immune responses.

  • The inflammatory reflex, a prototypical neural mechanism that modulates the immune system, consists of an afferent sensory arm that is activated by the products of sterile or infectious inflammation, and a motor arm, termed the cholinergic anti-inflammatory pathway, that inhibits pro-inflammatory cytokine release by the innate immune system.

  • The molecular mechanism of cytokine regulation by the inflammatory reflex depends on signal transduction by the nicotinic acetylcholine receptor α7 subunit (α7nAChR).

  • Administration of selective α7nAChR agonists or electrical stimulation of the inflammatory reflex inhibits pro-inflammatory cytokine release and confers protection against tissue damage.

  • The immune system is not autonomous because immune responses are influenced by the inflammatory reflex.

  • The inflammatory reflex maintains immune homeostasis as a set point function that influences the progression of inflammatory diseases.

Abstract

Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.

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Figure 1: Neural circuitry of the inflammatory reflex.
Figure 2: Mechanism of function of the efferent arc.
Figure 3: Functional anatomy of the inflammatory reflex.
Figure 4: The set point of the immune system.

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Acknowledgements

The author thanks S. Chavan, M. Rosas-Ballina, V. Pavlov, B. Volpe, P. Huerta, B. Diamond and S. Warren for helpful discussions. Work in the author's laboratory was supported in part by the National Institute of General Medical Sciences, one of the National Institutes of Health.

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K. Tracey is an inventor on patents related to the cholinergic anti-inflammatory pathway and is a consultant on this topic.

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Glossary

Sickness syndrome

The physiological and behavioural responses to the molecular products of infection or injury that can be triggered by the accumulation of pro-inflammatory cytokines in the brain. These include (but are not limited to) fever, acute phase responses, anorexia, weight loss, increased sleep, decreased social interaction, exploration, decreased sexual activity and altered hypothalamic, pituitary and autonomic output.

Pyrogen

An agent that is derived from either a pathogen or the host and that can cause fever in vivo. Examples of pyrogens include bacterial endotoxin and cytokines, such as tumour necrosis factor, interleukin-1 (IL-1) and IL-6.

Glomus cell

A type of epithelial cell located in the carotid body or in clusters (termed paraganglia) adjacent to the vagus and other autonomic nerves. A glomus cell can be activated by chemical changes in the cellular milieu to release dopamine or other neurotransmitters close to nerves.

Pathogen-associated molecular pattern

A microbial motif that can stimulate innate immune responses; for example, bacterial endotoxins, peptidoglycan, flagellin, double-stranded RNA and unmethylated CpG-containing DNA.

Toll-like receptor

A membrane receptor that is expressed by innate immune cells and that interacts with molecular products of infection or injury to initiate cytokine release and trigger inflammation.

Damage-associated molecular pattern

A molecule that is produced by the host and that can stimulate innate immune responses; for example, high-mobility group box protein, uric acid, heat shock proteins, heparin sulphate, hyaluronan fragments, ATP and DNA.

Nucleotide-binding oligiomerization domain (NOD)-like receptor

An intracellular pattern recognition receptor belonging to a family comprising 20 members that recognize endogenous or exogenous molecular products of infection or injury, several of which activate caspases that activate cytokine release and nuclear factor-κB signalling.

Sepsis

A systemic inflammatory syndrome that occurs after infection or injury and is characterized by a constellation of symptoms, including, but not limited to, alterations in body temperature, white blood cell count, heart rate, respiratory rate and organ function.

Catecholamines

A family of catechol-containing molecules, including adrenaline, noradrenaline and dopamine, which are produced by chromaffin cells of the adrenal medulla and are released as neurotransmitters from postganglionic fibres in the sympathetic nervous system.

Set point

The magnitude of a function in physiology and metabolism (for example, mean arterial blood pressure or body temperature) targeted as the output of homeostasis, such that deviations away from this target initiate compensatory reflexes to adjust the output back to that target.

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Tracey, K. Reflex control of immunity. Nat Rev Immunol 9, 418–428 (2009). https://doi.org/10.1038/nri2566

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