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Neuromodulation by the immune system: a focus on cytokines

Nature Reviews Immunology volume 21, pages 526–541 (2021)Cite this article

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Abstract

Interactions between the immune system and the nervous system have been described mostly in the context of diseases. More recent studies have begun to reveal how certain immune cell-derived soluble effectors, the cytokines, can influence host behaviour even in the absence of infection. In this Review, we contemplate how the immune system shapes nervous system function and how it controls the manifestation of host behaviour. Interactions between these two highly complex systems are discussed here also in the context of evolution, as both may have evolved to maximize an organism’s ability to respond to environmental threats in order to survive. We describe how the immune system relays information to the nervous system and how cytokine signalling occurs in neurons. We also speculate on how the brain may be hardwired to receive and process information from the immune system. Finally, we propose a unified theory depicting a co-evolution of the immune system and host behaviour in response to the evolutionary pressure of pathogens.

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Fig. 1: Initiation of behavioural responses.
Fig. 2: How the brain senses infection.
Fig. 3: Effects of distinct cytokines on different behavioural responses.
Fig. 4: Cytokine signalling to neurons.
Fig. 5: The close evolution between the immune system and the central nervous system.

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Acknowledgements

The authors thank S. Smith for editing the manuscript, A. Ampagliazzo for assistance with the figures and M. Lemieux for helping with the discussion of Fig. 4. This work was supported by grants from the US National Institutes of Health (MH108156, AT010416 and AG034113) to J.K.

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Authors and Affiliations

  1. Center for Brain Immunology and Glia (BIG), Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St Louis, MO, USA

    Andrea Francesca Salvador, Kalil Alves de Lima & Jonathan Kipnis

  2. Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA

    Andrea Francesca Salvador

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  1. Andrea Francesca Salvador
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Correspondence to Jonathan Kipnis.

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J.K. is a member of scientific advisory group for Puretech Health. The other authors declare no competing interests.

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Glossary

Autonomic

Autonomic behaviours are generally characterized as reflexive or unconscious behavioural responses to stimuli.

Proprioception

The perception of movement, position and force of limbs. Fast-conducting Aα fibres receive and transmit proprioceptive signals.

Interoception

The sensations or afferents that arise from visceral organs such as the gastrointestinal, urinary, circulatory or respiratory systems.

Neurotransmitters

Small molecules released from chemical synapses upon depolarization or in response to an increase in intracellular calcium concentrations in neurons. They are stored in small synaptic vesicles in the presynaptic terminal along with the enzymes crucial for its synthesis. They bind to receptors in the postsynaptic cell to influence gene expression and resting potential.

Neuropeptides

Small proteins produced with neurotransmitters in the presynaptic neuron but that are located in different cell compartments. They are present in larger granular vesicles and are released in response to specific stimuli. Their effect is of slow onset and longer lasting compared with neurotransmitters, and they act on G-protein-coupled receptors on the postsynaptic cell.

Dorsal root ganglia

A group of cell bodies or somas of sensory afferent fibres located along the spine. They carry information from the periphery to the central nervous system.

Synaptic transmission

The process by which neurons communicate; it can occur in two ways. Chemical transmission occurs via the release of neurotransmitters from the presynaptic terminal on depolarization to the postsynaptic cell. Electrical transmission, on the other hand, is bidirectional and occurs through clusters of gap junctions between adjacent cells. The gap junction channels allow the passage of electrical currents and small molecules.

Long-term potentiation

(LTP). The strengthening of synaptic connections between neurons that occurs after repeated high-frequency electrical stimulation.

Hypothalamic–pituitary–adrenal (HPA) axis

The major anatomical structures responsible for regulating stress responses. The HPA axis results in the release of cortisol, which promotes vascular activity, reduces immune responses, restricts inflammation and maximizes resources to protect the organism from damaging effects of stress.

Synaptic scaling

The process of calibrating the neuronal synapses to maintain stable or homeostatic firing rates.

Morris water maze

Used to test the hippocampal-dependent learning and memory of rodents. It comprises two parts: spatial acquisition and reversal. In spatial acquisition, the animal is allowed to navigate a swimming arena with opaque water where a hidden platform is located. It must use distal, spatial cues to find the hidden platform. The animals are tested daily after being placed in random start locations. The time it takes for the animal to find the platform is then recorded across the testing days. In reversal, the hidden platform is relocated to the opposite quadrant, and the animal’s ability to find the platform is tested.

Inhibitory neurons

Typically release inhibitory neurotransmitters such as GABA, which leads to the hyperpolarization of the postsynaptic cell.

Three-chamber sociability assay

Tests the sociability of rodents. The test animal is placed in a three-chamber box, and, because rodents are typically social animals, they will display preference for a novel mouse compared with a novel object. The time spent in each chamber either with the novel mouse or the novel object is then recorded.

Dural meninges

The outermost layer of the meninges, which is a membranous structure that lines the skull and surrounds the central nervous system. Lymphatic vessels that drain the cerebrospinal fluid are located in the dural meninges.

Elevated plus maze

A behavioural task that assesses anxiety-like behaviour in rodents. It uses a plus-shaped elevated apparatus with two open arms and two closed arms. Rodents typically show a tendency for dark, enclosed spaces as they hide from predators, and they have an unconditioned fear of heights and open spaces. Increased time spent on the open arms suggests a reduction in anxiety-like behaviour.

Open field test

Measures the activity and exploratory behaviour of rodents. It can also be used to test for anxiety-related behaviour. The typical behaviour of rodents is to spend more time in close proximity to the walls compared with the open area. Increased time spent in the open area indicates less anxiety-like behaviour.

Excitatory glutamatergic neurons

Release glutamate, an excitatory neurotransmitter, to the postsynaptic cell, which causes its depolarization.

Y-maze test

Used to assess the natural predisposition of rodents to explore novel environments. The test animal is allowed to freely move across the three arms of the maze, and the number of new arm entries is measured as the animal does not prefer to enter the arm that has been visited recently.

Glymphatic system

The astrocyte-dependent system of movement of cerebrospinal fluid and interstitial fluid across the brain parenchyma to clear metabolic waste.

Subarachnoid space

The space between the arachnoid mater and the pia mater, which are two of the layers of the meninges. This space is filled with cerebrospinal fluid.

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Salvador, A.F., de Lima, K.A. & Kipnis, J. Neuromodulation by the immune system: a focus on cytokines. Nat Rev Immunol 21, 526–541 (2021). https://doi.org/10.1038/s41577-021-00508-z

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