Neuronal Regulation of Immunity in the Skin and Lungs

doi:10.1016/j.tins.2019.05.005

Trends in Neurosciences

Volume 42, Issue 8, August 2019, Pages 537-551

https://doi.org/10.1016/j.tins.2019.05.005 Get rights and content

Highlights

Barrier tissues, such as the respiratory tract and skin, are major sites where swift communication between the peripheral nervous system and immune system occurs.
Recent insights have uncovered the molecular mechanisms by which nerves regulate tissue-resident immune cells, including innate lymphoid cells (ILCs) and mast cells.
Bacterial, fungal, and parasitic pathogens can directly signal to peripheral sensory nerves to induce neuroimmune interactions during infection of barrier tissues.
Neuroimmune interactions are involved in the exacerbation of many chronic inflammatory diseases, including asthma, COPD, AD, and psoriasis.
Immune cells in the lungs and skin can be positively or negatively modulated by the nervous system, depending on the type of peripheral sensory or autonomic nerves – representing neuroimmune regulatory switches.

The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma.

Section snippets

The Nervous and Immune Systems: Allies Working under Duress

Our barrier tissues are under constant assault from a variety of environmental threats, including noxious chemicals, thermal changes, mechanical injury, and microbial pathogens. The nervous and immune systems are specifically armed to combat these assailants to maintain homeostasis and to coordinate host defense. Mammalian barrier tissues including the skin, lungs, and gut are innervated by the PNS that serves to detect stimuli, including harmful ones, to respond to them, and to regulate

Neuroimmune Interactions at Barrier Tissues

Mammalian barrier tissues (e.g., skin, cornea, respiratory tract, gastrointestinal tract) interface with the environment, and must discern between innocuous and noxious stimuli, as well as maintaining homeostasis and integrity under changing conditions. The immune and nervous systems are tasked to carry out these essential functions. The immune system uses innate and adaptive mechanisms for host defense. The nervous system uses sensory neurons to induce protective nociceptive neural reflexes

Neuroimmune Interactions That Regulate Barrier Function

Barrier functions in the lungs and the skin are important in maintaining homeostasis and preventing infection. In mucosal surfaces such as the lung, CGRP, a neuropeptide from nociceptor neurons, has been found to regulate mucus production, which is a key aspect of barrier function 12., 13.. Nociceptor neurons also mediate barrier leakiness from the lung parenchyma into the blood during bacterial infection [14]. Mechanisms such as tight junction regulation, antimicrobial peptide production,

Neuroimmune Interactions in the Skin

The skin is one of the largest organs in the human body, and its integrity is necessary for homeostasis, protecting barrier function, and combating invading dangers such as pathogens. The nerve fibers innervating the skin are in close proximity to skin structural and functional cells, including keratinocytes, fibroblasts, endothelial cells, Schwann cells, and resident immune cell populations [16]. The cutaneous sensory nerve fibers (CSNFs), which innervate both the dermal and epidermal layers,

Neuroimmune Interactions in the Respiratory Tract

Gas exchange with the external atmosphere occurs in the lungs. During respiration, the lung epithelial surface acts as a barrier surface that comes into direct contact with the environment [46]. With the constant risk of exposure to harmful substances, detection of these potential dangers and pulmonary immunity against them are important. Nerves are therefore crucial in quickly detecting harmful substances to coordinate immune responses, which ultimately can limit the magnitude of lung

Concluding Remarks and Future Perspectives

Barrier tissues including the skin and respiratory tract are constantly exposed to the outside environment as well as to threats to our health and internal homeostasis. These tissues are therefore heavily innervated, and the nervous system is poised to quickly detect insults and in turn recruit the immune system and communicate with it. This establishes crucial neuroimmune crosstalk that is necessary for maintenance of barrier function and host defense. Although there are some shared features

Outstanding Questions

What is the integrative logic of neural control of immunity in barrier surfaces? Although it is well established that both the sensory and autonomic branches of the peripheral nervous system control immunity, the biological advantages for why some peripheral neural signals activate immune responses whereas others suppress them remains unclear. Understanding how neural signals are integrated by the immune system as a whole and within individual cell types is an important future research topic.

Acknowledgments

The laboratory of I.M.C. is funded by National Institutes of Health (NIH) grants F31 AI138384-01A (to K.J.B), NIH/National Center for Complementary and Integrative Health (NCCIH) DP2AT009499 (to I.M.C.), NIH/National Institute of Allergy and Infectious Diseases (NIAID) R01AI130019 (to I.M.C.), and the Chan Zuckerberg Initiative (to I.M.C.). Select images were adapted from Servier Medical Art (www.servier.com).

Glossary

Antigen-presenting cells (APCs): cells that present antigens in complex with MHCs on their surfaces to T cells.
Bronchoalveolar lavage fluid (BALF): the fluid that results from a diagnostic procedure in which cells and other components from bronchial and alveolar spaces are obtained for various studies or diagnoses. BALF is typically analyzed to diagnose lung diseases.
Dermal dendritic cells (dDCs): APCs located in the skin dermal layer, which process and present antigens on their cell surface to T

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Trends in Neurosciences

ReviewNeuronal Regulation of Immunity in the Skin and Lungs

Highlights

Section snippets

The Nervous and Immune Systems: Allies Working under Duress

Neuroimmune Interactions at Barrier Tissues

Neuroimmune Interactions That Regulate Barrier Function

Neuroimmune Interactions in the Skin

Neuroimmune Interactions in the Respiratory Tract

Concluding Remarks and Future Perspectives

Outstanding Questions

Acknowledgments

Glossary

Cell

Trends Immunol.

Immunity

Auton. Neurosci.

Toxicol. Lett.

J. Invest. Dermatol.

Med. Hypotheses

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Am. Acad. Dermatol.

Immunity

Cell Rep.

Cell Host Microbe

Cell

Curr. Opin. Pharmacol.

Eur. J. Pharmacol.

Neuron

Biochim. Biophys. Acta

Pulm. Pharmacol. Ther.

Am. J. Pathol.

Trends Neurosci.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Allergy Clin. Immunol.

Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence

J. Intern. Med.

Neuronal–immune system cross-talk in homeostasis

Science

Neural regulation of immunity: molecular mechanisms and clinical translation

Nat. Neurosci.

Crosstalk between the nociceptive and immune systems in host defence and disease

Nat. Rev. Neurosci.

Vaso-dilator axon-reflexes

Q. J. Exp. Physiol.

Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin

Br. J. Pharmacol. Chemother.

Autonomic nervous system and immune system interactions

Compr. Physiol.

The effects of calcitonin gene-related peptide on submucosal gland secretion and epithelial albumin transport in the ferret trachea in vitro

Br. J. Pharmacol.

Proximal airway mucous cells of ovalbumin-sensitized and -challenged brown Norway rats accumulate the neuropeptide calcitonin gene-related peptide

Am. J. Physiol. Lung Cell. Mol. Physiol.

Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia

Nat. Med.

Interactions between keratinocytes and somatosensory neurons in itch

Handb. Exp. Pharmacol.

The neuroimmune connection interferes with tissue regeneration and chronic inflammatory disease in the skin: stress and neuroimmune plasticity

Ann. N. Y. Acad. Sci.

Skin innervation: important roles during normal and pathological cutaneous repair

Histol. Histopathol.

Sympathetic skin response: basic mechanisms and clinical applications

Clin. Auton. Res.

The skin-resident immune network

Curr. Dermatol. Rep.

TRPA1 channels: molecular sentinels of cellular stress and tissue damage

J. Physiol.

Skin neurogenic inflammation

Semin. Immunopathol.

Sensory TRP channels contribute differentially to skin inflammation and persistent itch

Nat. Commun.

Review
Neuronal Regulation of Immunity in the Skin and Lungs