Pain and immunity: implications for host defence

Abstract

Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain.

Figure 1.. Neuro-immune interactions at peripheral nerve terminals and spinal cord in pain.

a) During inflammation, immune cells (mast cells, macrophages/monocytes, neutrophils and T cells) release mediators (cytokines, chemokines, lipid mediators and growth factors) that act on peripheral nerve terminals of nociceptor neurons. Action potentials are transduced via the dorsal root ganglia (DRG) to the spinal cord and relayed to the brain to be processed as pain. b) In the spinal cord dorsal horn, neuroimmune interactions contribute to central mechanisms of pain. Primary DRG nociceptive afferents (presynaptic) release glutamate, ATP and chemokines from their central terminals, mediating neurotransmission to second order postsynaptic neurons [G] that relay signals to the brain. T cells, microglia and astrocytes also produce pro-inflammatory cytokines and growth factors that act on both presynaptic and postsynaptic nerve terminals to increase neurotransmission and mediating central pain sensitization.

Figure 2.. Molecular mechanisms of immune-driven pain.

Immune cells release mediators that are directly sensed by nociceptor terminals to modulate neuronal excitation and pain transduction. Interleukin 1β (IL-1 β), tumor necrosis factor (TNF), nerve growth factor (NGF), prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and bradykinin bind their cognate receptors expressed by nociceptor terminals to mediate neuronal firing. Receptor mediated signaling cascades through PI3K, p38, PKA and SRC lead to phosphorylation of TRP ion channels TRPV1 and TRPA1, as well as the voltage-gated sodium channels (Na_v1.8 and Na_v1.9), leading to changes in gating properties of these ion channels. Phospholipase C (PLC) is activated downstream of TrkA or B2R, mediating hydrolysis of the inhibitory molecule phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 in turn mediates intracellular calcium release that sensitizes TRPV1 and TRPA1 activity. Immune mediators can also induce the upregulation of trafficking of ion channels to the membrane or increased transcriptional expression of these ion channels. The overall result of these immune-mediated pathways in nociceptors is the lowering of the threshold for responses to mechanical or thermal stimuli leading to increased pain sensitivity.

Figure 3.. Molecular mechanisms of microbial-driven pain.

Nociceptors can directly detect microbial pathogens and their products. S. aureus directly activates nociceptors through N-formyl peptides and the pore forming toxins (PFTs) α-haemolysin, PSMα3 and γ-haemolysin AB. Streptococcus pyogenes activates neurons through streptolysin S, which is a peptide toxin that also mediates cell lysis. In neurons, PFTs induce rapid cation influx and subsequent depolarization leading to pain production. Lipopolysaccharides (LPS), a major cell wall component of Gram-negative bacteria, also activates nociceptors through either neuronal TLR4 or directly gating of the TRPA1 ion channel. A subset of sensory neurons also expresses TLR5, whose cognate ligand is bacterial flagellin expressed by gram-negative bacteria. Candida albicans, a fungal pathogen, activates nociceptors through zymosan. Zymosan is a major cell wall component of fungi. Mycobacterium ulcerans, a skin pathogen that causes Buruli ulcer, silences pain by secreting a mycolactone that cause neuronal hyperpolarization by inducing angiotensin II receptor signaling. Herpes viruses invade sensory neurons and can cause significant pain following reactivation in syndromes such as post-herpetic neuralgia. Many molecular mechanisms remain to be determined for pathogen-induced pain though it is now clear that nociceptors, like immune cells, are able to directly respond to pathogen-derived molecules.

Figure 4.. Nociceptors regulate inflammation through neural-vascular and neuro-immune interactions.

a) Nociceptors release neuropeptides (such as substance P, CGRP and PACAP) from peripheral nerve terminals that act on the vasculature to drive ‘neurogenic inflammation’. Substance P activates NK1R on endothelial cells to promote vascular permeability and edema. CGRP acts via the CALCRL-RAMP1 receptor complex on vascular and lymphatic smooth muscle cells to promote relaxation and acts on endothelial cells to release nitric oxide, leading to vasodilation. b) Nociceptors release substance P, which acts on monocytes and macrophages via NK1R and downstream ERK-p38 MAPK-mediated NF-κB activation to drive expression of pro-inflammatory cytokines (left). CGRP acts on CALCRL-RAMP1 to drive cAMP-PKA-dependent modulation of CREB to upregulate IL-10 and inducible cAMP early repressor (ICER)-dependent transcriptional repression of pro-inflammatory cytokines (right). c) Nociceptors release CGRP, which decreases neutrophil recruitment to the lungs and skin and inhibits the ability of neutrophils to opsonophagocytose and kill bacteria. d) Substance P activates the Mgprb2 receptor on mast cells leading to mast cell degranulation and proinflammatory mediator release. e) CGRP from nociceptive neurons drives IL-23 production by dermal dendritic cells which in turn leads to activation of γδ T cells and IL-17 production (left). The neuropeptide VIP activates its receptor VPAC2 on Type II innate lymphoid cells (ILC2) to drive production of IL-5 and IL-13 (right). f) CGRP binds RAMP1 on dendritic cells to inhibit dendritic cell migration and activation, decreasing Th1 cell differentiation. In contrast, CGRP potentiates dendritic cell polarization of Th2 cell differentiation. CGRP can also acts via RAMP1 to increase IL-4 production by T cells directly to amplify the Th2 response.