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Neuroimmune circuits in inter-organ communication

Nature Reviews Immunology volume 20, pages 217–228 (2020)Cite this article

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Abstract

Studies in recent years have uncovered the crucial function of neuroimmune interactions in maintaining tissue homeostasis and protection. Immune and neuronal cells are often colocalized at defined anatomical sites, forming neuroimmune cell units, where both cell types coordinate their responses. In addition, even when located at distant sites, neuronal cells can receive signals from and provide signals to peripheral immune cells. As such, neuroimmune interactions are found across multiple organs and have recently emerged as important regulators of physiology. In this Review, we focus on the impact of bidirectional neuroimmune interactions in tissue biology, organ physiology and embryonic development. Finally, we explore how this fast-evolving field is redefining the tenets of inter-organ and intergenerational communications.

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Fig. 1: Neuroimmune crosstalk in the skin.
Fig. 2: Neuroimmune crosstalk in the lungs.
Fig. 3: Neuroimmune crosstalk in the gut.
Fig. 4: The gut–brain axis and the maternal gut–fetal brain axis.

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Acknowledgements

This work was supported by the Simons Foundation Autism Research Initiative (J.R.H.), the Jeongho Kim Neurodevelopmental Research Fund (J.R.H.), the Pew Scholar for Biomedical Sciences (J.R.H.), the US National Institutes of Health (grant R01MH119459) (J.R.H), the European Research Council (647274) (H.V.-F.), the Fundação para a Ciência e Tecnologia Portugal (H.V.-F.) and the Paul G. Allen Frontiers Group (H.V.-F.).

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Authors and Affiliations

  1. Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA

    Jun R. Huh

  2. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

    Jun R. Huh

  3. Champalimaud Research, Champalimaud Centre for the Unknown, Champalimaud Foundation, Lisbon, Portugal

    Henrique Veiga-Fernandes

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  1. Jun R. Huh
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J.R.H. and H.V.-F. both wrote and edited the manuscript.

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Correspondence to Jun R. Huh or Henrique Veiga-Fernandes.

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Glossary

Substance P

A neuropeptide of 11 amino acids in length belonging to the tachykinin family, formed by differential splicing of the preprotachykinin A gene (TAC1). Substance P is widely distributed throughout the nervous system but has been best appreciated as an important neurotransmitter in nociceptive pathways.

Nociceptor neurons

Sensory neurons that are activated by noxious or damaging stimuli. Nociceptor neurons are classified according to their ability to respond to mechanical, thermal and chemical stimuli. Free nerve endings in the periphery serving as receptive sites extend from neuronal cell bodies in the dorsal root or cranial nerve ganglia.

Nociception

The neural process of encoding noxious mechanical, thermal and/or chemical stimuli that occurs in afferent fibres, which send signals to the central nervous system.

Cholinergic neurons

Neuronal cells that mostly communicate via the neurotransmitter acetylcholine.

Dorsal root ganglia

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These neurons are pseudo-unipolar in nature, meaning that they have one axon with two processes: one peripheral axonal branch that innervates the tissues of the body to receive sensory information and one axonal branch that sends nerve impulses to the spinal cord. Dorsal root ganglia also contain satellite glia and macrophages that can modulate the function of sensory neurons.

Pulmonary neuroendocrine cells

(PNECs). Specialized epithelial cells that are present in the airways. Neuroendocrine cells can be found as solitary cells or associated in cell clusters called pulmonary neuroepithelial bodies. Neuroendocrine cells receive neuronal input that controls the release of endocrine molecules.

Vagus nerve

The nerve that connects the brainstem to the rest of the body. It contributes to the autonomic nervous system, which consists of the parasympathetic and sympathetic arms.

Enteric glial cells

A type of peripheral glia that are similar to astrocytes of the central nervous system. Among other functions, they maintain the structural integrity of the nervous system, provide trophic support to neurons, insulate one neuron from another and can clear debris.

Sympathetic catecholaminergic neurons

Sympathetic neurons are normally assumed to be part of the peripheral nervous system, but many of these neuronal cell bodies are present in the central nervous system. Sympathetic neurons of the spinal cord communicate with peripheral sympathetic neurons. In response to this stimulus, postganglionic neurons release catecholamines that bind adrenergic receptors on target cells inducing ‘fight-or-flight’ responses.

Blood–brain barrier

A physiological barrier between blood vessels and brain parenchyma. The barrier is formed by specialized tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane and an additional membrane formed from astrocyte feet and microglial cells, known as the glial limitans.

Aryl hydrocarbon receptor

(AHR). A cytosolic, ligand-dependent transcription factor that translocates to the nucleus following the binding of specific ligands, which include dietary and microbial metabolites. AHR participates in the differentiation of regulatory T cells, T helper 17 (TH17) cells and intraepithelial intestinal γδ T cells, and is required for the secretion of IL-22 by TH17 cells. More recently, AHR has been shown to have crucial roles in the development and function of lymphoid tissue inducer cells and group 3 innate lymphoid cells.

Astrocytes

The most abundant type of cell in the brain, named for their characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, such as supporting the formation and pruning of neuronal synapses.

Basolateral amygdala

A brain region extensively studied for its role in fear learning.

Segmented filamentous bacteria

A Gram-positive, spore-forming, non-culturable, Clostridia-related bacterium (provisionally named Candidatus savagella (of the Clostridiaceae family)) that resides in the terminal ileum in direct contact with intestinal epithelial cells and that induces the expression of IL-17A, IL-22 and IgA in the host.

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Huh, J.R., Veiga-Fernandes, H. Neuroimmune circuits in inter-organ communication. Nat Rev Immunol 20, 217–228 (2020). https://doi.org/10.1038/s41577-019-0247-z

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