Neuro-immune crosstalk and allergic inflammation

Abstract

The neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positive-feedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.

Figure 1. The interaction between sensory neurons and immune cells.

Immune cell–derived inflammatory mediators and noxious stimuli activate neurons via ion channels and various receptors for these mediators. Activated neurons release neuropeptides, which directly affect immune cells and regulate inflammatory responses. SP, substance P.

Figure 2. Neuro-immune interactions in different tissues.

Immune cells and neurons colocalize and interact with each other in local tissues. The effects of the interaction differ depending on the tissue. A detailed explanation can be found in the main text. LCs, Langerhans cells; LTB4, leukotriene B4; MBP, major basic protein; M2AChR, muscarinic 2 acetylcholine receptor; NA, noradrenaline.

Figure 3. The neuronal regulation of asthma.

Sympathetic neuron–derived NA suppresses ILC2-mediated type 2 inflammation via β2ARs located on ILC2s and induces the relaxation of smooth muscle cells. Parasympathetic neuron–derived acetylcholine (ACh) suppresses ILC2s via α7AChR and induces the contraction of smooth muscle cells via muscarinic 3 acetylcholine receptor (M3AChR). Eosinophils block the M2AChR suppressing the negative feedback loop of ACh. Sensory neuron–derived neuropeptides, including VIP, activate ILC2s and Th2 cells, which enhances type 2 inflammation. IL-5 activates the terminals of sensory neurons and induces the further release of VIP. NMU also directly activates ILC2s, leading to type 2 inflammation. Blocking the activation of sensory neurons using QX-314, a voltage-gated sodium channel blocker, inhibits the release of neuropeptides and attenuates type 2 inflammation. PNECs also produce CGRP and GABA, thereby activating ILC2s and directly inducing goblet cell hyperplasia in the airway. TRPs, transient receptor potential channels.