Mechanisms and Therapeutic Relevance of Neuro-immune Communication

Abstract

Active research at the frontiers of immunology and neuroscience has identified multiple points of interaction and communication between the immune system and the nervous system. Immune cell activation stimulates neuronal circuits that regulate innate and adaptive immunity. Molecular mechanistic insights into the inflammatory reflex and other neuro-immune interactions have greatly advanced our understanding of immunity and identified new therapeutic possibilities in inflammatory and autoimmune diseases. Recent successful clinical trials using bioelectronic devices that modulate the inflammatory reflex to significantly ameliorate rheumatoid arthritis and inflammatory bowel disease provide a path for using electrons as a therapeutic modality for targeting molecular mechanisms of immunity. Here, we review mechanisms of peripheral sensory neuronal function in response to immune challenges, the neural regulation of immunity and inflammation, and the therapeutic implications of those mechanistic insights.

Keywords: afferent nerves; autoimmune and inflammatory disease; bioelectronic medicine; cytokines; efferent nerves; inflammation; inflammatory reflex; neuro-immune communication; reflexes in immunity; vagus nerve.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1. Anatomy of sensory neurons with a role in neuro-immune interaction

Sensory neurons with cell bodies in the dorsal root ganglia are somatosensory and visceral. Somatosensory neurons, innervating the skin, joints and muscles, and visceral neurons, innervating the gastrointestinal track, pancreas, liver, lungs, heart and other organs enter the spinal cord via the dorsal horn. In the spinal cord central axonal terminals of these neurons make synaptic contacts with interneurons and relay neurons transmitting the signals to the brainstem and other brain areas. Vagus sensory neurons originate in the nodose ganglia (anatomically divided into nodose and jugular ganglia in rats and humans) and innervate visceral organs, including gastrointestinal tract, pancreas, liver, lungs, heart and other organs. Most of their central axons terminate in the nucleus tractus solitarius (NTS), with projections to other brainstem and forebrain areas. The activity of somatosensory and visceral neurons communicating peripheral information to the CNS is altered in inflammatory and autoimmune conditions affecting the innervated areas in visceral and somatic organs and tissues.

Figure 2. Molecular mechanisms at the immune-sensory neuron interface

Pathogens or tissue injury results in the release of inflammatory mediators, such as pro-inflammatory cytokines (tumor necrosis factor (TNF), interleukin-1β, IL-6, IL-17), nerve growth factor (NGF), prostaglandins (PGE2), serotonin and histamine, by immune cells. Both pathogens and inflammatory mediators can modulate the activity of sensory neurons in the local area. Cytokines and other inflammatory mediators act on receptors expressed on peripheral axonal terminals of sensory neurons, including cytokine receptors, G protein-coupled receptors (GPCR), and tyrosine kinase receptor type 1 (TrkA). Similar to immune activation, pathogens can cause sensory neuronal activation mediated by pathogen-associated molecular patterns (PAMP) interaction with pattern recognition receptors (PRR) (such as TLR4) on neurons. The secretion of N-formyl peptide and α-hemolysin by the pathogen S. aureus can directly activate sensory neurons by binding to formyl peptide receptor 1 (FPR1) or ion channel oligomerization and depolarization. Activation of sensory neurons by pathogens or inflammatory mediators leads to generation of secondary messengers such as Ca2+ and cAMP, which in turn activates intracellular kinases such as adenylyl cyclase, protein kinase A (PKA) and C (PKC), and mitogen activated protein kinase (MAPK). Activation of this signaling cascade results in action potential generation and plasticity associated gene regulation. It also decreases the threshold for activation of key neuronal receptors such as transient receptor potential cation channel subfamily A member 1 (TRPA1), TRPV1, and TRPM8 as well as the voltage-gated sodium channels Nav1.7, Nav1.8 and Nav1.9 by noxious stimuli, e.g. hypersensitization. Neuronal activation by pathogens and inflammatory stimuli also causes the release of neuropeptides, which in turn modulate inflammatory responses. Vasoactive intestinal peptide (VIP), substance P and calcitonin gene-related peptide (CGRP) are involved in the generation of neurogenic inflammation. CGRP, somatostatin and galanin suppress lymphadenopathy and inflammation in bacterial infection.

Figure 3. Anatomy of efferent autonomic neurons with a role in immune regulation

Efferent vagus nerve neurons originate in the dorsal motor nucleus of the vagus (DMN), and nucleus ambiguus (NA) in the brainstem medulla oblongata. These preganglionic cholinergic neurons give projections to visceral organs in the thoracic and abdominal cavity, including the lungs, heart, liver, gastrointestinal tract, kidneys and pancreas. They interact with postganglionic vagal neurons in proximity or within the innervated organs, and these neurons release predominantly acetylcholine. Vagus nerve preganglionic neurons also terminate in the celiac ganglia and the superior mesenteric ganglion where the splenic nerve originates. Splenic nerve catecholaminergic neurons release norepinephrine (NE) in spleen. NE interacts with β2-adrenergic receptors on choline acetyltransferase (ChAT)+ CD4+ T cells and causes release of acetylcholine. The locus coeruleus (LC) and the rostroventrolateral medula (RVLM) are brain regions associated with sympathetic control. RVLM give descending projections to sympathetic neurons in the spinal cord. Sympathetic preganglionic (cholinergic) fibers project to paravertebral (not shown) and prevertebral ganglia, including the celiac ganglia. Postganglionic fibers release predominantly NE in the innervated visceral organs. Postganglionic fibers from paravertebral ganglia innervate the lungs and the heart (not shown). Postganglionic fibers from perivertebral ganglia innervate the, liver, gastrointestinal tract, kidneys, pancreas and other visceral organs. Sympathetic preganglionic fibers also innervate the adrenal medulla and stimulate the secretion of epinephrine (Ep) from chromaffin cells.

Figure 4. Molecular mechanisms of acetylcholine and catecholamine mediated regulation of cytokine release

Norepinephrine binding to β-adrenergic receptors on macrophages and other immune cells triggers intracellular signaling, including activation of intracellular cyclic AMP (cAMP) and protein kinase A (PKA). This activation results in inhibition of NF-κB activation and attenuation of pro-inflammatory cytokine production. Acetylcholine (ACh) interacts with the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages and other immune cells. This interaction triggers intracellular signaling involving, activation of adenylyl cyclase 6 (AC6), which leads to inhibition of NF-κB activity and suppression of TNF and other pro-inflammatory cytokine production. Through another mechanism, ACh binding to α7nAChR leads to interaction between α7nAchR and JAK2, which results in phosphorylation of STAT3. Phosphorylated STAT3 dimers translocate to the nucleus to induce suppression of pro-inflammatory cytokines. In addition, activation of immune cells with extracellular ATP leads to rapid influx of acetylcholine into the cytoplasm. Cytoplasmic acetylcholine attenuates mitochondrial DNA release via mitochondrial α7nAchR and subsequently inhibits inflammasome activation and IL-1β cytokine release.