Essential Neuroscience in Immunology

Abstract

The field of immunology is principally focused on the molecular mechanisms by which hematopoietic cells initiate and maintain innate and adaptive immunity. That cornerstone of attention has been expanded by recent discoveries that neuronal signals occupy a critical regulatory niche in immunity. The discovery is that neuronal circuits operating reflexively regulate innate and adaptive immunity. One particularly well-characterized circuit regulating innate immunity, the inflammatory reflex, is dependent upon action potentials transmitted to the reticuloendothelial system via the vagus and splenic nerves. This field has grown significantly with the identification of several other reflexes regulating discrete immune functions. As outlined in this review, the delineation of these mechanisms revealed a new understanding of immunity, enabled a first-in-class clinical trial using bioelectronic devices to inhibit cytokines and inflammation in rheumatoid arthritis patients, and provided a mosaic view of immunity as the integration of hematopoietic and neural responses to infection and injury.

Figure 1. Mechanisms by which acetylcholine inhibits cytokine release

Extracellular acetylcholine (Ach) inhibits cytokine production through nicotinic acetylcholine receptor subunit α7 (α7nAChR), which is expressed by cytokine-producing immune cells. α7nAchR signal transduction results in phosphorylation of CREB, which increases expression of cfos that inhibits NF-κB activity leading to suppression of cytokine production. Interaction of α7nAchR with JAK2 leads to phosphorylation of STAT3. Phosphorylated STAT3 dimers translocate to the nucleus to induce suppression of cytokine production. 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.

Figure 2. Neural reflex circuits in immunity

(A) The inflammatory reflex. The efferent signals generated in the vagus nerve are transmitted via the celiac ganglion to the spleen to acetylcholine-producing (ChAT+) T cells. Acetylcholine (Ach) attenuates cytokine production by macrophages in α7nAChR-dependent manner. (B) Splenic neural circuits modulating antibody production. Activation of vagus nerve culminates into stimulation of the adrenergic splenic nerve resulting in release of norepinephrine (NE) leading to accumulation of CD11+ B cells in the marginal zone and decreased antibody production. (C) The Gateway reflex. Soleus muscle contractions activates afferent neural signals that culminate into efferent adrenergic signals at the lumbar 5 level modulating the expression of CCL20 by the endothelial cells and providing an important control mechanism that gates the entry of pathogenic T cells into the CNS. (D) Neural reflexes in cancer. In a model of prostate cancer, adrenergic nerves promote tumor growth via norepinephrine release and cholinergic nerves within the tumor tissue enhance tumor metastasis by releasing acetylcholine. (E) Nociceptive reflexes in lung. The by-products of allergic inflammatory response activate sensory neurons and immune cells in the lung. IL-5 released by activated immune cells directly activates Nav1.8 positive nociceptors and induces the release of vasoactive peptide VIP. CD4+ T cells and Type 2 innate lymphoid cells respond via a VIP receptor, and produce elevated levels of IL-5, IL-13 and other cytokines that activate IgE production by B cells. VIP signaling and IgE activates and recruits immune cells to amplify the inflammatory responses in the lung. (F) Sensory axon-axon reflex. Bacterial-derived N-formylated peptides or toxins activate sensory neurons resulting in a release of neuropeptides (galanin, substance P, CGRP) that directly suppress innate immune activation. (G) Vagus nerve-adrenal reflex. Activation of the sciatic nerve results in the efferent vagus nerve signals culminating in the adrenal medulla leading to increased production of dopamine that targets dopaminergic type 1 receptors and suppresses systemic inflammation. (H) Enteric neural reflexes. Neuronal adrenergic signals modulate the switch of muscularis macrophages to tissue protective phenotype M2 by signaling through β2 adrenergic receptors. Enteric neurons and muscularis macrophages regulate homeostasis by production of CSF-1 and BMP respectively. Direct electrical stimulation of the vagus nerve results in acetylcholine release by cholinergic myenteric neurons leading to attenuation of inflammation in α7nAChR manner.