Molecular and Functional Neuroscience in Immunity

Abstract

The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.

Keywords: brain; cytokines; immunity; inflammation; nervous system; vagus nerve.

Figure 1

Communication between the nervous system and the immune system. The nervous system and the immune system communicate in response to pathogen invasion, tissue injury, and other homeostatic threats. Macrophages, neutrophils, monocytes, T lymphocytes, and other immune cells detect the presence of pathogen fragments and tissue injury molecules and release cytokines and other signaling molecules. These alterations in peripheral immune homeostasis are detected by sensory neurons residing in the dorsal root ganglia (DRG) and vagus nerve afferent neurons, which signal the spinal cord and the brain. Pathogens also directly activate afferent neurons. These signals are integrated in the central nervous system with descending signaling via sympathetic and efferent vagus nerve fibers with the release of catecholamines and acetylcholine, respectively. These neurotransmitters interact with immune cells and control immune cell function and responses. Other neurotransmitters released from neurons also play a role in immune control. The hypothalamic-pituitary-adrenal (HPA) axis with the release of corticosteroids also provides a conduit of brain–immune regulation.

Figure 2

Functional neuroanatomy and molecular mechanisms of sensing pathogens and immune mediators. Sensory neurons originating from the dorsal root ganglia (DRG) are somatosensory, innervating the skin, joints, and muscles, and visceral, innervating the liver, lungs, gastrointestinal tract, pancreas, heart, and other organs. These neurons enter the spinal cord via the dorsal horn and make synaptic contacts with interneurons and relay neurons (not shown) that signal to the brain, including the thalamus. Sensory vagus nerve fibers originating in the nodose ganglia innervate visceral organs and transmit signals to the nucleus tractus solitarius (NTS), with projections to other brainstem and forebrain areas (not shown). Inflammatory mediators, such as cytokines, are released by immune cells in response to tissue injury or pathogens and activate sensory neurons in the local area. Inflammatory mediators interact with sensory neurons through cognate receptors, expressed on these neurons. Neuronal activation results in a signaling cascade leading to action potential generation and may also decrease the activation threshold for nociceptive receptors [e.g., transient receptor potential cation channel subfamily members (TRPV1, TRPA1)] as well as the voltage-gated sodium channel Na_v receptors (Na_v1.7, Na_v1.8 and Na_v1.9) by noxious stimuli. Pathogen fragments can also activate sensory neurons directly by binding to the pattern recognition receptors (PRRs) (such as TLR4) on neurons. In addition, pathogens such as Staphylococcus aureus activate nociceptors by releasing N-formyl peptide and α-hemolysin, which bind to formyl peptide receptor 1 (FPR1) or ion channels. The release of neuropeptides, including calcitonin gene-related peptide (CGRP), galanin, somatostatin, substance P, and vasoactive intestinal peptide (VIP) in an axon-reflex fashion regulates immune responses. Some components of this figure are adapted from Reference 18.

Figure 3

Functional neuroanatomy and molecular mechanisms of regulating immune responses. (a) Sympathetic preganglionic fibers originating in the spinal cord terminate into paravertebral (not shown) and perivertebral ganglia releasing acetylcholine (ACh; not shown). Postganglionic catecholaminergic fibers innervate visceral organs and release norepinephrine (NE). Efferent sympathetic output to the adrenal medulla induces the secretion of epinephrine (EP) from chromaffin cells. The dorsal motor nucleus of the vagus (DMN) and nucleus ambiguus (not shown) in the brainstem medulla oblongata are major sources of efferent vagus nerve fibers. Cholinergic preganglionic vagus efferent fibers innervate visceral organs, where they interact with postganglionic fibers that release acetylcholine as a principal neurotransmitter. Preganglionic efferent vagus fibers also terminate in the celiac ganglia and the superior mesenteric ganglion, where the splenic nerve originates. The splenic nerve releases norepinephrine, which in turn activates the release of acetylcholine from the choline acetyl transferase (ChAT)-positive CD4⁺ T cells. (b) Acetylcholine and NE regulate cytokine release by immune cells activated in response to tissue injury or pathogen invasion. Acetylcholine binds to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages and other immune cells. This interaction activates intracellular signaling, involving suppression of NF-κB activity and activation of the JAK2/STAT3 pathway, which results in suppression of proinflammatory cytokine production. In addition, acetylcholine binds to the α7nAChR expressed on mitochondria and suppresses mitochondrial DNA release, which in turn inhibits inflammasome activation. Norepinephrine and epinephrine bind to the β₂-adrenergic receptors on macrophages and other immune cells and induce intracellular signaling, involving cyclic AMP and protein kinase A (PKA), which results in suppression of NF-κB activity and proinflammatory cytokine release. Some components of this figure are adapted from Reference 18. Other abbreviations: cAMP, cyclic adenosine monophosphate; DMN, dorsal motor nucleus of the vagus; mt, mitochondrial; PRR, pattern recognition receptor.

Figure 4

The model of the immunological homunculus. Alterations in immune homeostasis in visceral organs and the skin are communicated to the spinal cord and the brain via sensory neurons residing in the dorsal root ganglia and vagal afferent neurons. It is important to consider that in this communication, specific neuronal populations (shown in different colors) are engaged in processing signals for the presence of pathogens, antigens, cytokines, and other immune cell–signaling molecules. These are listed as 1, 2, 3, and 4, but theoretically the list could be extended. This sensory information arrives in the nucleus tractus solitaries (NTS), rostroventrolateral medulla (RVLM), locus coeruleus (LC), hypothalamus (HT), thalamus (Th), and different cortex regions. Brain areas including the cortex, Th, HT, LC, RVLM, and dorsal motor nucleus of the vagus (DMN) are interconnected in orchestrating immunoregulatory (motor) output. Most of these brain regions participate in processing both sensory and motor immune-related information. It is possible that specific areas and nuclei in these regions (shown in different colors) are viscerotopically, somatotopically, and functionally organized in relation to peripheral immune information. The amygdala (Am), the hippocampus (HC), and other brain regions (question marks) may also be components of immune-related brain organization. Brain-derived immunoregulatory (motor) output is communicated to the periphery via sympathetic and vagus nerve efferent fibers, releasing norepinephrine (NE) and epinephrine (EP), acetylcholine (ACh), and other neurotransmitters and regulates a myriad of innate and adaptive immune responses in visceral organs, including the lymphatics, and the skin. It is conceivable that peripheral organs with a role in immunity are viscerotopically and somatotopically represented in the cortex by analogy with the classical model of homunculus. This schematic representation aims to present basic principles of the model. Some aspects, including brain neurotransmitter networks with a role in immune regulation, are not presented. The model should be further developed based on molecular mapping of neural circuitries and precise characterization of the roles of these and other unknown brain regions in immune regulation.