Pathological pain and the neuroimmune interface

Abstract

Reciprocal signalling between immunocompetent cells in the central nervous system (CNS) has emerged as a key phenomenon underpinning pathological and chronic pain mechanisms. Neuronal excitability can be powerfully enhanced both by classical neurotransmitters derived from neurons, and by immune mediators released from CNS-resident microglia and astrocytes, and from infiltrating cells such as T cells. In this Review, we discuss the current understanding of the contribution of central immune mechanisms to pathological pain, and how the heterogeneous immune functions of different cells in the CNS could be harnessed to develop new therapeutics for pain control. Given the prevalence of chronic pain and the incomplete efficacy of current drugs--which focus on suppressing aberrant neuronal activity--new strategies to manipulate neuroimmune pain transmission hold considerable promise.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1. Physiological pain processing

a | Nociceptive signals are transmitted from the periphery by nociceptive sensory neurons (first-order primary afferent neurons) the peripheral terminals of which are clustered with ion channels, including transient receptor potential channel subtypes (TRPA, TRPM and TRPV), sodium channel isoforms (Nav), potassium channel subtypes (KCNK) and acid-sensing ion channels (ASICs). The transduction of external noxious stimuli is initiated by membrane depolarization due to the activation of these ion channels. b | Action potentials are conducted along the axons of nociceptive Aβ- and C-fibres, through the cell body in the dorsal root ganglion to the axonal terminals, which form the presynaptic element of central synapses of the sensory pathway in the spinal dorsal horn or hindbrain. The central terminals of Aβ- and C-fibres synapse with interneurons and second-order nociceptive projection neurons, primarily within the superficial laminae of the spinal dorsal horn. The axons of second-order nociceptive projection neurons decussate at the spinal cord level, joining the ascending fibres of the anterolateral system, and project to brainstem and thalamic nuclei, transferring information about the intensity and duration of peripheral noxious stimuli. c | No single brain region is essential for pain, but rather pain results from the activation of a distributed group of structures. Third-order neurons from the thalamus project to several cortical and subcortical regions (black arrows) that encode sensory-discriminative (for example, somatosensory cortex (S1)), emotional (for example, anterior cingulate cortex (ACC), amygdala (CeA) and insular cortex (IC)), and cognitive (for example, pre-frontal cortex (PFC)) aspects of pain. Several brainstem sites are also known to contribute to the descending modulation of pain (grey arrows) including the periaqueductal grey (PAG), locus coeruleus (LC) and rostral ventromedial medulla (RVM).

Figure 2. Initiation of central immune signalling

Damage to or high-threshold activation of first-order neurons by noxious stimuli induces the release of ATP, CC-chemokine ligand 2 (CCL2), CCL21 and neuregulin 1 (NRG1), as well as endogenous danger signals to initiate central immune signalling in the dorsal horn of the spinal cord. CCL2 is released and rapidly upregulated by neurons following depolarization, and signals via its cognate receptor CC-chemokine receptor 2 (CCR2) on microglia. CX3C-chemokine ligand 1 (CX3CL1) is liberated from the neuronal membrane by matrix metalloproteinase 9 (MMP9) and MMP2 and by microglial cell-derived cathepsin S (CatS) and signals via CX3C-chemokine receptor 1 (CX3CR1), which is expressed by microglia. CCR2 and CX3CR1 signalling also induces the expression of integrins (such as intercellular adhesion molecule 1 (ICAM1) and platelet endothelial cell adhesion molecule (PECAM1)) by endothelial cells, allowing the transendothelial migration of T cells. Neuronal cell release of CCL21 stimulates local microglia via CCR7, and infiltrating T cells are activated via CXCR3. ATP induces microgliosis via the purinergic receptors P2X3R, P2X7R, P2Y12R and P2Y13R. Microglia express Toll-like receptor 2 (TLR2) and TLR4 leading to activation of the MYD88 pathway after detection of endogenous danger signals, such as heat shock protein 60 (HSP60), HSP90, high mobility group box 1 (HMGB1) and fibronectin. Following the detection of such signals, many intracellular pathways are recruited including SRC family kinases (SRC, LYN and FYN), MAPKs (extracellular signal-regulated kinase (ERK), p38 and JUN N-terminal kinase (JNK)) and the inflammasome. This leads to phenotypic changes, increased cell motility and proliferation, altered receptor expression, the activation of transcription factors, such as nuclear factor-κB (NF-κB), and the production of inflammatory mediators (such as interleukin-1β, (IL-1β), IL-18, tumour necrosis factor (TNF) and brain-derived neurotrophic factor (BDNF)). Interleukin-1 receptor (IL-1R1) signalling reduces microglial cell expression of G protein-coupled receptor kinase 2 (GRK2), which is a negative regulator of G protein-coupled receptors (GPCRs), including chemokine receptors. This leads to sustained GPCR signalling, and the exaggerated and prolonged production of pro-inflammatory mediators. The release of soluble mediators also provides a feedback mechanism by which further immune cells are activated.

Figure 3. Neuroimmune enhancement of nociception

Soluble mediators released by reactive immunocompetent cells in the central nervous system diffuse and bind to receptors on presynaptic and postsynaptic terminals in the spinal dorsal horn to modulate excitatory and inhibitory synaptic transmission, resulting in nociceptive hypersensitivity. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), CC-chemokine ligand 2 (CCL2), reactive oxygen species (ROS) and interferon-γ (IFNγ) increase glutamate (Glu) release from central terminals, partly due to the activation of transient receptor potential channel subtypes (TRPV1 and TRPA1), and functional coupling between interleukin-1 receptor 1 (IL-1R1) and presynaptic ionotropic glutamate receptors (NMDAR). TNF, IL-1β, IL-6 and ROS decrease GABA (γ-aminobutyric acid) and glycine (Gly) release by inhibitory interneurons. IL-1β and CCL2 also increase AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) signalling, and TNFR1 signalling increases the expression of Ca2+-permeable AMPA receptors (AMPARs). TNF increases NMDAR activity through the phosphorylation (P) of extracellular signal-regulated kinases (ERKs), while IL-17 and ROS induce phosphorylation of the NR1 receptor subunit in spinal cord neurons. IL-1β increases the calcium permeability of NMDAR through activation of SRC family kinases and also via phosphorylation of the NR1, NR2A and NR2B subunits. CXCL1 signalling via CXCR2 induces rapid activation of neuronal ERK and CREB. Brain-derived neurotrophic factor (BDNF) signalling via TRKB downregulates the potassium-chloride cotransporter KCC2, increasing the intracellular Cl− concentration and weakening the inhibitory GABAA and glycine channel hyperpolarization of second-order nociceptive projection neurons. Prostaglandin E2 (PGE2) signalling at the EP2 receptor activates protein kinase A (PKA), thereby inhibiting glycinergic neurotransmission via GlyR3. IL-1R1 signalling reduces neuronal expression of G protein-coupled receptor kinase 2 (GRK2), a negative regulator of G protein-coupled receptors (GPCRs), including chemokine and prostaglandin receptors, leading to sustained neuronal GPCR signalling. TNF and IL-1β downregulate astrocyte expression of the Glu transporters excitatory amino acid transporter 1 (EAAT1) and EAAT2, leading to enhanced glutamatergic transmission. CCR2, CC-chemokine receptor 2; GABAR, GABA receptor.