Neuro-immune interactions in inflammation and host defense: Implications for transplantation

Abstract

Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine.

Keywords: basic (laboratory) research/science; immune regulation; immunosuppression/immune modulation; innate immunity; neurology.

Figure 1. Nociceptor Sensory Neurons Crosstalk with Immune Cells in Pain and Inflammation

(a) Nociceptor neurons are activated by immune cells and their molecular mediators. Pathogens, tissue injury, and other inflammatory insults trigger a immune response. These immune cells including neutrophils, mast cells, macrophages and T cells release molecular mediators including pro-inflammatory cytokines, nerve growth factor (NGF), prostaglandin E2 (PGE2), serotonin and histamine. Nociceptor sensory neurons express receptors for these immune-derived mediators, including cytokine receptors, G-protein coupled receptors, and tyrosine kinase receptor type 1 (TrkA). Sensory neurons also express pathogen recognition receptors including FPR1, and toll-like receptors (TLRs). The bacterial toxin α-hemolysin also forms pores in neuronal membranes to directly activate neurons. Upon ligand binding, generation of second messenger signaling through cAMP or Ca²⁺ can lead to intracellular phosphorylation cascades that produce changes in the gating properties of TRPV1, TRPA1 cation channels and the voltage-gated sodium channels Nav1.7, Nav1.8, and Nav1.9. These ion channels are critical for pain production, and their sensitization during inflammation leads to increased action potential generation, neuronal plasticity, and transcriptional changes in nociceptor neurons that results in pain. (b) Nociceptor neurons play an important role in regulating immune cell function by communication with them through neuropeptides. In peripheral nerve terminals, neuropeptides including substance P, calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) are stored in dense-core vesicles. During inflammation, generation of action potentials, local axonal reflexes, and Ca²⁺ entry into these terminals leads to SNARE-mediated vesicle release of these neuropeptides. These neuropeptides then regulate tissue inflammation by activating receptors present on smooth muscle cells, endothelial cells, macrophages, dendritic cells and innate lymphoid cells (ILCs). These neuro-immune interactions mediate host-pathogen responses, asthma, inflammatory bowel disease, arthritis, and other inflammatory disease conditions.

Figure 2. Vagal Efferent Anatomy and the Cholinergic Anti-inflammatory Reflex

Visceral organs in the thoracic and abdominal cavity including the lungs, heart, liver, stomach, gut, pancreas and kidneys are innervated by parasympathetic and sympathetic nerves. The efferent portion of the vagus nerve, which is the preganglionic parasympathetic fiber, originates from the dorsal motor nucleus (DMN) and nucleus ambiguous (NA) in the medulla oblongata and project to postganglionic fibers in proximity with or within visceral organs. Both the preganglionic and postganglionic vagal fibers are cholinergic. Postganglionic vagal fibers release acetylcholine (Ach) into viscerl organs to regulate smooth muscle activity, gut motility, and gland secretion. In the spinal cord, sympathetic neurons received descending projects from the locus coeruleus (LC) and the rostroventrolateral medulla (RMLM) in the brainstem. The sympathetic preganglionic fibers interact with postganglionic fibers within the paravertebral and prevertebral ganglia. Postganglionic fibers from paravertebral and prevertebral ganglia innervate visceral organs in the thorax (lungs, heart) and the abdominal cavity (liver, stomach, gut, kidneys, pancreas) respectively, and release norepinephrine (NE). Sympathetic preganglionic fibers also innervate the adrenal medulla directly and stimulate the secretion of epinephrine (EP) from chromaffin cells. Both vagal and sympathetic preganglionic fibers give projections to the splenic nerve within the celiac and superior mesenteric ganglion. In a cholinergic anti-inflammatory reflex, NE released by the splenic nerve acts on choline acetyltransferase (ChAT)+ CD4+ T cells through β2-adrenergic receptors. These T cells release Ach to regulate macrophage production of TNF-α and other cytokines.