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.
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The authors thank F. A. Pinho-Ribeiro for helpful discussions. I.M.C. receives funding from the US National Institutes of Health (NIH) under grants NCCIH DP2AT009499 and RO1AI130019, the Chan-Zuckerberg Initiative and the Harvard Stem Cell Institute. S.U. receives support from the NIH under T32 AI007061.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sensory nerves that are activated by noxious or potentially damaging stimuli. Two classes of nerve fibres, Aδ and C fibres, make up nociceptors in humans, and nociceptors are classified according to their ability to respond to mechanical, thermal and chemical stimuli. Free nerve endings in the periphery serving as receptive sites extend from neuronal cell bodies in the dorsal root or cranial nerve ganglia.
- Presynaptic nerve
Anatomically, the neuron before the synapse that delivers the chemical neurotransmitter to the postsynaptic neuron. In figure1, presynaptic refers to peripheral sensory neurons projecting from the peripheral tissues to the spinal cord whose cell bodies are located in the dorsal root ganglia. These presynaptic neurons transmit pain signals from the periphery to the spinal cord.
- Dorsal root ganglia
(DRG). Structures that contain clusters of sensory neurons that reside adjacent to the spinal cord, which include nociceptors. These neurons are pseudo-unipolar in nature, meaning that they have one axon with two processes: one peripheral axonal branch that innervates the tissues of the body to receive sensory information and one axonal branch that sends nerve impulses to the spinal cord. DRG also house satellite glia and macrophages that can modulate the function of sensory neurons.
An increased sensitivity to a normally painful mechanical or thermal stimuli.
- Postsynaptic neurons
Neurons located after the synapse that receives the chemical transmitter from the presynaptic neuron. In figure1, postsynaptic refers to second-order neurons in the dorsal horn of the spinal cord that project to the brain. These neurons transmit the nociceptive signals received from presynaptic neurons.
A painful sensation caused by a normally innocuous stimuli. For example, mechanical allodynia can be caused by light touch or stroking.
The pungent ingredient from chili peppers that elicits the burning sensation of pain. Capsaicin is a ligand that binds to the transient receptor potential subfamily V member 1 (TRPV1) ion channel on nociceptors to drive pain sensation.
- Substance P
A neuropeptide of 11 amino acids in length belonging to the tachykinin family. It is formed by differential splicing of the preprotachykinin A gene (TAC1). Substance P is widely distributed throughout the nervous system but has been best appreciated as an important neurotransmitter in nociceptive pathways.
- Calcitonin gene-related peptide
(CGRP). A neuropeptide formed by the alternative splicing of the calcitonin gene. It has two isoforms, α-CGRP and β-CGRP, which differ in three amino acids and are transcribed from distinct genes (CALCA and CALCB). Classically, α-CGRP has been thought to be the primary form expressed in the peripheral and central nervous systems, while β-CGRP is mainly found in the enteric nervous system. Of note, while the primary association of CGRP is with the nervous system and particularly with nociceptive signalling, expression has been reported in non-neuronal cells as well.
- M2 macrophage
An alternatively activated or anti-inflammatory macrophage. Multiple anti-inflammatory cytokines such as IL-4, IL-13 or IL-10 drive M2 macrophage polarization. While M1 macrophages drive host inflammation via release of pro-inflammatory cytokines, M2 macrophages mediate the resolution of inflammation and the wound healing.
The traditional direction of action potentials in nerves, running along the axon away from the neuronal soma. For a peripheral sensory neuron, orthodromic means propagation of action potentials towards central nerve terminals and the spinal cord.
The opposite direction of traditional nerve impulses. For a peripheral sensory neuron, antidromic refers to back-propagation of action potentials towards peripheral nerve endings.
- Vasoactive intestinal peptide
(VIP). A peptide of 28 amino acids in length belonging to the glucagon/secretin family and encoded by the VIP gene in humans. VIP acts via the G protein-coupled receptors VPAC1 and VPAC2. It is broadly expressed throughout the nervous system and peripheral tissues and has been best appreciated as a neurotransmitter implicated in gastrointestinal motility.
- Pituitary adenylyl cyclase-activating polypeptide
(PACAP). A peptide with close homology to vasoactive intestinal peptide (VIP) that is encoded by the ADCYAP1 gene in humans and has two biologically active forms, PACAP-27 and PACAP-38. PACAP has high affinity for three classes of G protein-coupled receptors: VPAC1, VPAC2 and PAC1. Like VIP, PACAP is broadly expressed in the nervous system and peripheral tissues.
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Baral, P., Udit, S. & Chiu, I.M. Pain and immunity: implications for host defence. Nat Rev Immunol 19, 433–447 (2019). https://doi.org/10.1038/s41577-019-0147-2
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