Neuroimmune Interaction: A Widespread Mutual Regulation and the Weapons for Barrier Organs

Abstract

Since the embryo, the nervous system and immune system have been interacting to regulate each other's development and working together to resist harmful stimuli. However, oversensitive neural response and uncontrolled immune attack are major causes of various diseases, especially in barrier organs, while neural-immune interaction makes it worse. As the first defense line, the barrier organs give a guarantee to maintain homeostasis in external environment. And the dense nerve innervation and abundant immune cell population in barrier organs facilitate the neuroimmune interaction, which is the physiological basis of multiple neuroimmune-related diseases. Neuroimmune-related diseases often have complex mechanisms and require a combination of drugs, posing challenges in finding etiology and treatment. Therefore, it is of great significance to illustrate the specific mechanism and exact way of neuro-immune interaction. In this review, we first described the mutual regulation of the two principal systems and then focused on neuro-immune interaction in the barrier organs, including intestinal tract, lungs and skin, to clarify the mechanisms and provide ideas for clinical etiology exploration and treatment.

Keywords: barrier organ; immune; nerve; neuroimmune crosstalk; neuropeptide; neurotransmitter.

FIGURE 1

Neuroimmune circuits in skin. Immune cells activate receptors and channels on sensory neurons in the skin by secreting cytokines, chemokines, and lipids, leading to itching and pain. Nerve endings can also regulate immune cells by releasing SP, CGRP, VIP and other neuropeptides. Neuropeptides and factors can act on the skin and blood vessels, causing inflammation and edema. Pathogens can stimulate nociceptors directly or by inflammatory cytokines from immune cells. Pruritus receptors’ activation cause scratch, which leads to the destruction of keratinocytes with TSLP released, triggering amplification effect. Nociceptors are mainly involved in Th1 and Th17 immune responses, while pruritus receptors are mainly involved in Th2 immune responses.

FIGURE 2

Neuroimmune circuits in lungs. The epithelium, nerves and immunity of the lung together constitute the airway barrier. Various allergens, bacteria and parasites stimulate and interact with different nerves to upload signals and regulate immunity. For example, LPS of bacteria combines with TLRs of sensory nerves to promote the release of neuropeptides, while worms act on sympathetic nerves to secrete neurotransmitters and mainly regulate ILC2s. Immune cells transmit immune signals to the nerve by releasing cytokines, forming a closed-loop of nerve and immunity. Moreover, immune cells synthesize nerve growth factor to promote nerve growth and increase nerve exposure in the airway.

FIGURE 3

Neuroimmune communication in the intestinal tract. In the gut, sensory nerves express receptors that recognize various stimuli, pathogens, and cytokines. Activated sensory nerves release different neurotransmitters that interact with immune cells. In addition, exogenous sympathetic and vagus nerves also participate in inflammatory responses by releasing corresponding neurotransmitters.