Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation

Abstract

Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.

Keywords: inflammation; neuroimmunology; nociceptor; pain; sensory neuron.

Figure 1. Immune Cells Release Mediators that Produce Peripheral Sensitization of Nociceptor Sensory Neurons and Pain

During inflammation, tissue resident and recruited immune cells secrete molecular mediators that act on the peripheral nerve terminals of nociceptor neurons to produce pain sensitization. In these neurons, specific cytokine, lipid, and growth factor receptor intracellular signaling pathways lead to phosphorylation and/or gating of ion channels Na_v1.7, Na_v1.8, Na_v1.9, TRPV1 and TRPA1, leading to increased action potential generation and pain sensitivity. Upon degranulation, mast cells release Interleukin 5 (IL-5), serotonin (5-HT), histamine and nerve growth factor (NGF) that act on IL-5R, 5-HT2, histamine receptor 2 (H2), TrkA, on nociceptor neurons, respectively, to produce pain sensitization. Nociceptor neurons are also sensitized by tumor necrosis factor alpha (TNFα), IL-1β and IL-6 produced by mast cells, macrophages, and neutrophils. TNFα receptor 1 (TNFR1) activation leads to phosphorylation of Na_v1.9 channels. Activation of IL-1 receptor 1 (IL-1R1) increases TRPV1 expression by nociceptors, while IL-6 binds gp130 on nociceptors and this increases expression of both TRPV1 and TRPA1, enhancing responsiveness to heat and reactive chemicals. Prostaglandin E₂ (PGE₂) released by macrophages and other innate immune cells also sensitize nociceptor neurons through PGE₂ receptors 1–4 (EP1-4). Th17 cells and γδT cells can also sensitize nociceptor neurons through IL-17A release and neuronal IL-17RA signaling.

Figure 2. Microglia and T Cells Mediate Central Sensitization of Pain in the Spinal Cord

Microglia are the resident immune cells of the central nervous system, and play a key role in mediating central pain sensitization. Primary afferent nociceptor neurons transduce action potentials from the periphery to the dorsal horn of spinal cord, where synapses between first order and second order neurons occur. In chronic inflammatory or neuropathic pain, nociceptors release of mediators including caspase 6 (Casp 6), adenosine triphosphate (ATP), chemokine ligand 2 (CCL2), tumor necrosis factor alpha (TNFα), colony-stimulating factor-1 (CSF-1), and calcitonin gene-related peptide (CGRP) that activate microglia. Microglia produce inflammatory mediators including interleukin 1 beta (IL-1β), TNFα, brain-derived neurotropic factor (BDNF), and prostaglandin E₂ (PGE₂) which sensitize first and second order neurons. This process is called spinal sensitization and contributes to chronic pain. T cells also infiltrate the spinal cord and cross-talk with microglia cells and neurons to amplify pain sensitivity. Upon peripheral nerve injury, primary afferent nociceptor neurons release CX3CL1 into the spinal cord which induce dorsal horn microglia to produce TNFα, which activates astrocytes to produce CCL2 and CXCL1 that induce changes in spinal cord neurons leading to central sensitization. Oligodendrocytes produce IL-33 and cross-talk with microglia and astrocytes to increase pain sensitivity.

Figure 3. Nociceptor Neurons Release Neuropeptides that Regulate Vascular, Innate and Adaptive Immune Cell Function

While noxious stimuli generates pain through afferent signals to the central nervous system, calcium influx in the peripheral nerve terminals also causes local release of dense-core vesicles containing neuropeptides. These neuropeptides have potent effects on the vasculature and immune cells to regulate tissue inflammation: (a) The neuropeptide calcitonin gene-related peptide (CGRP) activates the RAMP1/CalcRL receptor complex in vascular smooth muscle cells (SMC) to promote muscle relaxation and vasodilation. Substance P (SP), another nociceptive neuropeptide, activates tachykinin receptor 1 and 2 (TACR1/2) in vascular endothelial cells to increase vascular permeability, which results in edema formation. CGRP and SP also act on lymphatic endothelial cells and SMC to regulate lymph flow. (b) CGRP binds RAMP1 in macrophages and dendritic cells (DC), leading to downstream PKA activity, which affects cytokine production by two different pathways. The first pathway (left side) occurs by induction of the transcriptional inducible cAMP early repressor (ICER) and inhibition of tumor necrosis factor alpha (TNFα) expression. The second pathway (right side) occurs by induction of the transcription factor cAMP response element binding (CREB) and induction of interleukin 10 (IL-10) expression. (c) CGRP increases IL-23 production by dermal dendritic cells (CD301b+ dDCs) that, in turn, promotes IL-17 production by Th17 cells and γδT cells. (d) Vasoactive intestinal peptide (VIP) activates its receptor VPAC2 expressed by innate lymphoid cells and Th2 cells and stimulates these cells to produce IL-5 and IL-13, important mediators of allergic reactions that cause degranulation of eosinophils and mast cells.

Figure 4. Nociceptor Neurons Actively Contribute to Inflammatory Disease Conditions

Nociceptor neurons actively modulate the immune response and disease progression in inflammatory conditions. (a) In the skin, nociceptor neurons play a role in driving dendritic cell activation and γδT cell IL-17 production in psoriasis-like inflammation. They also play a role in mediating oxazalone and FITC driven mouse models of contact dermatitis. Nociceptor neurons reduce skin host protection to Staphylococcus aureus infection, but promote skin immunity against Candida albicans (b) In joints, neurons regulate the severity of rheumatoid arthritis due to their effects in promoting Th17 cell responses and changes in vascular endothelial cells. (c) In the lungs, nociceptor neurons contribute to asthmatic airway inflammation and its deleterious effects by driving type 2 innate lymphoid cells and mediating bronchoconstriction. (d) In the gastrointestinal tract, nociceptor neurons regulate the progression of mouse models of colitis. While nociceptor neurons drive immunopathology (cytokine production and weight loss) through mechanisms related to substance P (SP) release and activation of the nociceptive ion channel TRPA1, they also reduce immunopathology through release of calcitonin gene-related peptide (CGRP) and activation of the cold-sensing ion channel TRPM8.