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Available online at

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ain and immunity

avier Guillota,b,∗, Luca Semeranoa,b, Patrice Deckera,c, Géraldine Falgaronea,b,arie-Christophe Boissiera,b

Sorbonne Paris Cité, EA 4222, Li2P, université Paris-13, 93000 Bobigny, FranceService de rhumatologie, CHU Avicenne, AP–HP, 125, rue de Stalingrad, 93009 Bobigny cedex, FranceInserm, EA 4222, Li2P, université Paris-13, 93000 Bobigny, France

r t i c l e i n f o

rticle history:ccepted 29 September 2011vailable online xxx

eywords:ociceptorseuropathic painllodyniaensitizationeuronlial cellatrophage

cell cell receptororsal root ganglionorsal horn

a b s t r a c t

Chronic neuropathic and inflammatory pain is a major public health problem. Nociceptors undergo sen-sitization, first in peripheral tissues then in the central nervous sytem, via neuroimmune interactionslinking neurons, glial cells (microglia and astrocytes), and immune cells. These interactions may eitherexacerbate or attenuate the pain and inflammation, which normally reach a state of equilibrium. Withmore powerful or longer lasting stimuli, specific profiles of microglial and, subsequently, astrocytic acti-vation in the dorsal horn play a key role in neuronal plasticity and transition to chronic pain. Recentinsights into the interactions between the nervous system and the immune system suggest a large num-ber of potential therapeutic targets that could be influenced either by targeted inhibition or by directingthe neuroimmune response toward the antiinflammatory and analgesic end of its spectrum.

© 2011 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie.

lasticityntegrated networkeciprocal communication

L-1�NF-�esolvins

. Introduction

The management of chronic pain is a major public health issue.owever, the mechanisms underlying chronic pain remain partlybscure [1,2]. Acute nociceptive pain occurs when powerful oroxious stimuli activate specialized sensory neurons (A� and Cociceptors) characterized by high activation thresholds. The nexttep is action potential transfer to the spinal cord, which sendsarning signals to the brain. In contrast, neuropathic pain, which

s relevant to chronic pain, is caused by traumatic, inflammatory,r dysmetabolic lesions of the peripheral or central nervous sys-em (CNS). Neuropathic pain is delayed and occurs in the absence

Please cite this article in press as: Guillot X, et al. Pain and immunity.

f any stimulus, due to nociceptor stimulation with a decrease inhe nociceptor activation threshold. The pain becomes autonomousnd loses its adaptive function associated with improved tissue

∗ Corresponding author.E-mail address: [email protected] (X. Guillot).

297-319X/$ – see front matter © 2011 Published by Elsevier Masson SAS on behalf of thoi:10.1016/j.jbspin.2011.10.008

recovery. The equivalent of neuropathic pain in animals is pro-longed behavioral hypersensitivity. Central integration is involved,with a role not only for the neuronal pathways, but also for theSchwann cells, satellite cells in the dorsal root ganglions, and cells ofthe innate and adaptive immune systems in the peripheral and CNS.The result is neuroimmune activation of the spinal cord microgliaand astrocytes. Neuropathic pain manifests as increased sensitiv-ity to heat and, more typically, as mechanical allodynia, which isan inappropriate painful response to a stimulus that does not nor-mally cause pain, with diffusion of the response to healthy adjacentor even contralateral tissues. Immune cells, in addition to beinginvolved in the genesis and control of inflammation, also triggersensitization of peripheral nociceptors and contribute to centralintegration of the pain signals by influencing spinal-cord synapticplasticity. Immune cells produce analgesic molecules (e.g., opi-

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oid peptides), antiinflammatory compounds, and lipid molecules,which promote resolution of the pain response [3]. By releasingmediators of inflammation and interacting with some of the neu-rotransmitters and their receptors, the immune cells, glial cells,

e Société Française de Rhumatologie.

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Table 1Treatment targets – stimulation of naturally occurring antiinflammatory and analgesic mechanisms.

Cells Target/Function Effect Drugs/Treatment trials References

Leukocytes, keratinocytes, RAsynovium/osteoarthritis (T cells,macrophages, fibroblasts)

Production of opioids (b-endorphin) triggered bychemokines (CX3CL1, CX3CL2)/endothelinreceptor (keratinocytes)

Inhibits IL-6 and IL-8 production by the synovialmembraneDecreases symptoms of collagen-induced arthritis

[39]

Monocytes, Th2 cellsActivated glial cells

Release of IL-10 and IL-4 Inhibits neuropathic pain in murine models (sciatic nerveconstriction)Neurone survival

Plasmidic DNA encoding IL-10encapsulated in a PGLA microparticle(intrathecal injection)

[40]

Immune cells (T cells andmacrophages) and glial cells

Canabinoid receptors CB1 and CB2 Inhibits chemotactism, the MAP kinase pathway, andtherefore the release of proinflammatory cytokinesDecreases spontaneous pain (animal models of peripheralnerve injury)

Selective CB2 agonists [41]

Microglia, macrophages Purinoceptor P2RX7 (stimulated by ATP) Release of glutamate-neuroprotective TNF�Inhibits excitotoxic cell deathResolves inflammation

[42]

MacrophagesGlial cells

Phagocytosis induced by TLR SOCS3 activation Clearance of apoptic cellsInhibition of proinflammatory cytokine release

[21–32]

Neutrophils, endothelial cells,activated immune cells

Proresolution lipid mediators: resolvins, lipoxins,neuroprotectins

RvE1: Adjuvant arthritis, decreases in intraarticularneutrophil infiltration, joint swelling, and expression ofproinflammatory cytokines and chemokines; inhibition ofTNF� effects on the TRVP1 and NMDA receptors and ofTNF� effects on dorsal horn neurons via ERK inhibitionRvD1: inhibits IL-1� production in the microgliaRvD2: Decreases neutrophil migration by inhibitingleukocyte-endothelium interactions in vivoSpares the protective and adaptive effects of inflammation(no increase in the infection risk)No effect on basal pain threshold

[43,44]

Astrocytes Glutamate transporters: GLT-1 and GLAST [30]

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Table 2Treatment targets – inhibition of proinflammatory and algesic mechanisms.

Cells Target/Function Effect Drugs/Treatment trials References

Microglial cells TLR4 Controls proinflammatory cytokine release and phagocytosisTLR4 inhibition in animal models of neuropathic pain: inhibitsneuropathic pain due to sciatic nerve injury, inhibits glialactivation by opioids, limits the risk of tolerance and adverserespiratory events

TLR4 antagonism [23,25]

Purinoceptors (stimulated by ATP)P2RX4P2RX2, P2RX3, P2RX7

Cell deathP2RX4 inhibition: diminishes mechanical allodynia after nerveinjuryInhibition of P2RX2, P2RX3, and P2RX7: decreases the response ofprimary sensory neurons, the release of proinflammatorycytokines, and mechanical hypersensitivity induced by nerveinjury

Inhibition of the P2RX4 receptorSelective inhibitors of theheteromultimers of P2RX2-P2RX3,P2RX3, and P2RX7

[42,45–47]

MMP and microglial iNOS inhibition, MAPkinase p38 phosphorylation, neuronalnecrosis and apoptosis

Limitation: no effect on pain hypersensitivity after nerve injury Minocycline [48]

Glial cells Inhibition of glial metabolism Decreases in proinflammatory cytokine release and neuropathicpain in animal models

FluorocitrateMAC-1-saporinTeriflunomide

Inhibition of phosphodiesterase Inhibits recent-onset pain and established hypersensitivityPotentiates the effects of opioids in rats

PropentofyllineAV-411 (ibudilast): Phase II

[49,50]

MAP kinases (p38, JNK, ERK) responsiblefor glial activation

Inhibition of MAP kinase p38 (subunit �): inhibits allodynia;production of IL-1, IL-6, and TNF in the spinal cord glia; andpotentiation of AMPA/NMDA currents in spinal-cord sectionsInhibition of JNK1: inhibits ipsi- and contralateral mechanicalallodynia and chronic inflammatory pain in adjuvant arthritis

Astrocytic JNK1 inhibitor: D-JNK1 [21,28,51]

Astrocytes Astrocytic glutamine synthetase Inhibitor: methionine sulfoximine

Macrophages, neurtrophils, glial cells,Schwann cells

Inhibition of proinflammatory cytokinesIL-15, endothelinIL-6TNF�IL-1�

Nociceptor sensitizationInhibition: effect on mechanical allodynia (murine models andcentral and peripheral neuropathic pain)Inhibition: effect on inflammatory hyperalgesia due to urate acidcrystal injection (mouse ankle) or gout

sIL-15 R�; bosentan and indocid(inhibition of endothelin)Gene transfer (soluble TNF-�R1fragment + viral vector) to thedorsal root ganglionRilonacept (ArcalystR): fusionprotein extracellulardomain + accessory human IL-1receptor protein

[52,53–55]

NeutrophilsDorsal root ganglion neurons

C5 receptor (C5aR) Inhibition: decreases pain and inflammation due to C5a injectioninto rat footpads, inhibits neutrophil recruitment and pain inzymosan-induced arthritisNo effect in synovial inflammation in RA (no information on pain)

PMX53 (C5a receptor antagonist) [11,57]

Schwann cellsMast cells

NGFTRKA receptor for NGF

Pain (knee osteoarthritis)Inhibition: decreases hyperalgesia in collagen- orzymosan-induced arthritisMurine models of inflammatory and neuropathic pain

Tanezumab: anti-NGF antibodies –Phase II; Phase III trials under wayVaccination: murine recombinantNGF + viral particleAnti TrkA antibody

[58,60]

Sensory neurons Calcium ionotropic channels:TRPA-1 blockadeTRPV-1 blockade

Blockade: decreases pain induced by TNF in adjuvant arthritis AP-18 (local injection)SB-366791 (intrathecal injection)

[18]

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Fig. 1. Peripheral nociceptor sensitization: a: mast cells and macrophages recruitedand activated after tissue injury release proinflammatory cytokines, chemokines,complement cascade effectors (C3a and C5a), and vasodilators (e.g., vasoactiveamines and bradykinine), thereby contributing to peripheral nociceptor sensi-tization via direct and indiret cell interactions. Nociceptor excitability can beexacerbated by bradykinin, histamine, neuropeptides, glutamate, serotonin, sub-stance P, prostaglandins, protons, K+, ATP, proinflammatory cytokines (most notablyIL-15, TNF-�, IL-1�, IL-6, IL-18, and IL-12), and nerve growth factor (NGF), producedin response to tissue injury, metabolic stress, or inflammation. TNF-� released by theSchwann cells induces MMP-9 (as does IL-15), which promotes macrophage migra-tion to the injury site via disruption of the blood-brain barrier (BBB) [10]; b: duringinflammation, NGF is released by many cell types and, by binding to its receptor(TrkA), promotes phosphorylation of transient receptor potential vanilloid receptor1 (TRPV-1), an ion channel with key effects in hyperalgesia. NGF also stimulatesthe release of inflammatory mediators by mast cell degranulation (bradykinin, his-tamine, PGE2, and NGF), thereby activating and sensitizing the nociceptors via directand indirect effects involving a positive-feedback loop [17]. IL-1� also regulates theincrease in NGF production by the Schwann cells [16]. Bradykinin production bymast cells induces TNF-� release, which triggers two nociceptive pathways, theIL-1�and prostanoid pathway and the CXC chemokine pathway (CINC-1/IL-18), therebyinducing the release of amines from the sympathetic system [8]; c: primary afferentneurons generate impulses that travel to neighboring nerve endings and induce therelease of vasoactive neuropeptides (substance P and calcitonin gene-related pep-tide [CGRP]), causing neurogenic inflammation that affects neutrophil recruitmentand mast cell degranulation. IL-1 can also bind to the nerve endings and induce therelease of substance P. Neutral endopeptidase limits neurogenic inflammation bydd

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matory pain, and C5a-induced hyperalgesia is diminished in

egrading substance P and CGRP [19]. Furthermore, substance P can promote theifferentiation of human memory CD4+ T cells to Th17 or Th1/Th17 cells [15].

nd neurons constitute an integrated network that coordinateshe immune responses and modulates pain pathway excitabil-ty, via mechanisms that constitute potential treatment targets,

ost notably for chronic pain [4]. Here, we will focus on patho-hysiological considerations and summarize the new therapeuticevelopments in two tables (Tables 1 and 2).

. Inflammation and sensitization of peripheralociceptors

Synergistic neuroimmune interactions promote sensitization toain and the development of chronic pain (Fig. 1). During these

nteractions, numerous soluble mediators can amplify the responsend increase the recruitment of immune cells. Damaged axonselease vasoactive mediators such as calcitonin gene-related pep-ide (CGRP), substance P, bradykinin, and nitric oxide, which causedema and hyperemia. These vascular changes allow invasion byirculating immune cells. The signaling pathways that link pri-ary sensory neurons, Schwann cells, and immune cells are closely

Please cite this article in press as: Guillot X, et al. Pain and immunity.

ntertwined into a complex network involving numerous cytokineswith both pro- and antiinflammatory effects), prostaglandins, andhemokines.

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2.1. Inflammation and involvement of the innate immune system

After an injury, the inflammatory response is triggered in partby the toll-like receptors (TLRs), which are receptors of the innateimmune system that recognize and bind to non-self pathogenicagents or to endogenous molecules released by damaged cells. TLRsare expressed by immune cells (monocytes, macrophages, den-dritic cells, and neutrophils) and by a number of related cells such askeratinocytes. Binding of TLRs to their ligands activates the NF-�Bsignaling pathway and results in the release of prioinflammatorycytokines [5].

2.2. Mast cells

Mast cell degranulation requires direct interaction with theperipheral nerve endings, via N-cadherin, a calcium-dependentadhesion protein that can be cleaved by the metalloproteinaseMT5-MMP of the peptidergic receptors in the dorsal root ganglion.In the adjuvant arthritis model, the absence of inflammatory ther-mal hyperalgesia in mice lacking the MT5-MMP gene establishesa key role for mast cell degranulation in inflammatory pain andin the development of dermal neuroimmune synapses [6]. Amongcompounds released during mast cell degranulation, histamine andbradykinin play a major role in nociceptor activation [7,8].

2.3. Macrophages

Resident macrophages and macrophages developed from cicu-lating monocytes play a predominant role in the initial immuneresponse to peripheral nerve injury. Macrophage counts increaseat the site of nerve lesions and correlate with the developmentof mechanical allodynia. Macrophage recruitment and activationis orchestrated by interactions between the chemokines CCL-2and 3 and their receptors CCR2, CCR1, and CCR5. Thus, expressionof the chemokine macrophage inflammatory protein-1� (MIP-1�) and its receptors CCR1 and CCR5 undergoes upregulation inmacrophages and Schwann cells after partial sciatic nerve liga-tion, which contributes to the development of neuropathic pain[9]. Some of the proinflammatory cytokines such as TNF� and IL-15 not only sensitize the nociceptors, but also allow the recruitmentof macrophages after a nerve injury [10]. Once recruited and acti-vated, the macrophages contribute to nociceptor sensitization byreleasing soluble mediators. Phagocytosis of degenerating axonsand myelin debris allows Schwann cell reorganization and axonregeneration.

2.4. The complement cascade

Complement plays a major role in inflammatory hyperalgesiaand neuropathic pain. C5a and C3a injection into the footpads of ratsor mice induces hyperalgesic behaviors via chemoattraction andstimulation of neutrophils, which bear the C5aR1 receptor (indirecteffect). C5a sensitizes the C fibers to thermal stimulation in mice,and C5a receptor mRNA is expressed by the dorsal root ganglionneurons, suggesting a possible direct effect on nociceptors [11,12].

2.5. Neutrophils

Neutrophils play a very early role in the immune responseto nerve lesions. Neutrophil migration is associated with inflam-

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neutrophil-depleted rats [11]. Although neutrophil infiltrationis short-lived and confined to the tissues adjacent to thelesion, neutrophils release cytokines, reactive oxygen species, and

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Fig. 2. Neuronal pathways involved in pain signal transmission [21]. Cross-sectionof the spinal cord and dorsal root ganglion: the ganglion contains pseudo-unipolarsensory neurons, each of which gives rise to a single axon, which divides in two,with one branch traveling to the periphery and the other to the dorsal horn, where it

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hemoattractants such as monocyte chemoattractant protein-1MCP-1).

.6. T cells

T cells also contribute to sensitize the peripheral nociceptors. Tells infiltrate the damaged sciatic nerve and dorsal root ganglion.n rats lacking T cells, the hyperalgesia and allodynia induced byerve lesions are diminished or abolished. Furthermore, IL-17 lev-ls are high in the rat spinal cord after nerve injury [13]. Th1 cellsromote the development of pain hypersensitivity by releasingroinflammatory cytokines (IL-2 and interferon-� [IFN�]), whereash2 cells produce the opposite effect by releasing antiinflammatoryytokines (IL-4, IL-10, and IL-13) [14]. A number of neuropeptidessubstance P, bradykinin, and CGRP) influence the immune cells.hus, substance P, whose expression is increased in joint fluid fromatients with rheumatoid arthritis (RA), exerts stimulant and proin-ammatory effects on many immune cells via its neurokinin-1eceptor (NK-1R) [15].

.7. Role for neurons and Schwann cells

Immune cells interact with damaged neurons and Schwannells. Damaged Schwann cells release mediators, such as nerverowth factor (NGF) [16], which promote axon growth and remyeli-ation and stimulate neuronal voltage-dependent receptors and

on channels, including transient receptor potential (TRP) chan-els, both directly and indirectly via mast cell degranulation [17].xperiments on mice lacking the gene for the TRP vanilloid recep-or 1 (TRPV-1) established that TRPV-1 played a central role inilateral thermal hyperalgesia to TNF�, whereas TRP ankyrin-1TRPA-1) played a crucial peripheral role in mechanical hyperalge-ia induced by TNF� in the adjuvant arthritis model [18]. Schwannells (and satellite microglial cells), as well as some of the sen-ory neurons, express chemokine receptors. Schwann cells produceeurotrophic factors, prostaglandins, and cytokines. The proinflam-atory cytokine cascade contributes to cause axonal damage and

lso modulates the activity and sensitivity of the nociceptors [19].ctivation of sensory-neurone TNF receptors and recruitment ofNF receptor-associated factors (TRAFs), which are intracellulardaptive proteins, lead to phosphorylation of mitogen-activatedrotein kinase p38 (MAP kinase p38) and Jun N-terminal kinaseJNK), which in turn activates the transcription factors NF�B andun [20]. This TNF-induced signaling pathway in sensory neuronsxerts a feedback effect on the immune cells, by inducing proteaseelease and by upregulating adhesion molecules, thus promotingacrophage infiltration and the production of proinflammatory

ytokines by macrophages. These interactions between immuneells and peripheral nerve cells promote axon survival and growthut also trigger the transition toward chronic pain, which sub-equently involves increasingly complex integration within theorsal root ganglion and spinal cord and, subsequently, in the entireNS (spinal cord then brain).

. Integration of pain signals

.1. Neuronal pathways

Peripheral inflammation induces persistent central sensitiza-ion with mechanical allodynia and thermal hyperalgesia (Fig. 2).he dorsal root ganglions are clusters of primary sensory neu-ons of the peripheral somatosensory system. They are adjacent

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o the spinal cord and send axons to the dorsal horn. The neuronodies within the ganglion are surrounded by small satellite glialells interconnected by a network of GAP-junctions, where numer-us paracrine interactions take place. Marked and/or prolonged

forms synapses with nociceptive interneurons and second-order projection neuronsinvolved in pain. The pain signal is integrated by the dorsal horn then transmittedto supraspinal targets.

nociceptive stimulation results in the release of substance P andglutamate in amounts sufficient to induce prolonged depolariza-tion of second-order neurons in the spinal cord, causing activationof neuronal NMDA calcium channels and the release of nitric oxideand prostaglandins, which in turn induce hyperexcitability and therelease of excessive amounts of neurotransmitters, the result beingpain signal amplification. This mechanism promotes pain sensiti-zation and the transition to chronic pain.

3.2. Activation of the central microglia and astrocytes

Glial cells (astrocytes and microglia) modulate synaptic func-tion and neuronal excitability and can play a deleterious and/orneuroprotective role in chronic pain [21] (Fig. 3). The early CNSglial response to peripheral nerve injury is dominated by activa-tion of the spinal cord microglia, and subsequently the astrocytesundergo activation and proliferation. The central glial cells are acti-vated in many pain processes in response to peripheral injury, andthey release mediators that amplify neuronal excitability and thepain response. These cells are responsible for the central integra-tion of pain signals, and glial plasticity may be the source of thetransition toward chronic neuropathic pain. The resident microgliaproliferate upon activation and exert both pro- and antiinflamma-tory effects. When the pain signal persists (chronic inflammationor nerve injury), glial activation can induce transcriptional modifi-cations in the dorsal horn, affecting neuronal function in the longterm. The activation signals are conveyed to the brain via periph-eral immune system activation and an afferent nervous signalconveyed by circulating immune cells [13] and cytokines. Severalanimal models of inflammatory pain, such as zymosan-inducedarthritis, are characterized by spinal-cord glial activation (upreg-ulated expression of CD11b, glial acid fibrillary protein [GFAP], andionized calcium-binding adapter molecule [Iba1]) and behavioralhyperalgesia. The glial overactivity is temporally and somatotopi-cally adapted to the inflammation- and pain-inducing stimulus.Three main signaling pathways mediate the recruitment of residentspinal-cord microglial cells and circulating monocytes to the dorsalhorn and their activation: interaction of the chemokine fractalkine

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with the CX3CR1 receptor, interaction of CCL2 with the CCR2receptor [22], and activation of the TLRs [23]. Microglial cells andastrocytes are immunocompetent cells derived from hematopoi-etic and neuroectodermal cells, respectively. They combat invading

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Fig. 3. Central integration of pain signals: neuroimmune synapse: a: upon thearrival of a nerve impulse, neuronal and immune mediators such as glutamate, ATP,substance P, CGRP, brain-derived neurotrophic factor (BDNF), IL-6, and CCL2 arereleased from the primary afferent nerve endings in the spinal cord. These media-tors interact with receptors located on postsynaptic nerve endings, the microglia,and astrocytes, thereby modulating glial activity. Neuregulin-1 (NRG-1), a growthand differentiation factor released by primary afferent nerve endings, binds to itstyrosine-kinase ErbB2 receptor expressed on microglial cells, inducing the activa-tion of these cells, the release of proinflammatory cytokines including IL-1�, anda chemoattractant effect [29]. CGRP release by the sensory neurons induces theproduction of IL-1� by glial cells, which consequently increase their production ofprostaglandin E2 (PGE2) via the cyclooxygenase 2 pathway (COX-2); b: activation ofTLRs expressed by glial cells induces proinflammatory cytokine release and phago-cytosis [23,24]. TLR2 and TLR4 are the main TLRs expressed by the microglia andtheir activation can result in the release of IL-1-�, TNF-�, and IL-6. In addition, glialcells perform phagocytosis and scavenge debris. Microglial TLRs may be activatedin part by debris from cells or from neurons undergoing apoptosis, such as fibronec-tine or heat-shock proteins (Hsp) 60 and 70. The chemokine CX3CL1 can be cleavedfrom the neuronal membrane by the protease cathepsin S produced by microglialcells or matrix metalloproteinases (MMPs) after peripheral nerve injury or neu-ronal activation. CX3CL1 thus released binds to its receptor CX3CR1 expressed onthe microglial cell membrane, causing phosphorylation of MAPK p38 within thesecells [26]. Neuronal expression of CCL2 triggers activation of the astrocytes andmicroglia, which express CCR2. Phosphorylation activating MAPK p38 or ERK in theglial cells can be induced by an increase in intracellular calcium in response to bind-ing of the purinoceptor P2RX4 with cleavage of pro-IL-1� by metalloproteinase-9(MMP-9) on the microglia (MMP-2 on astrocytes) [34]; c: astrocytes can be acti-vated, via the NMDA receptors of the postsynaptic neurons, by cytokines such asIL-18, substance P, CGRP, opioids (via the � receptor), or directly by glutamatevia the astrocyte metabotropic glutamate receptor, which increases mobilizationof intracellular calcium. Astrocyte activation induces several intracellular signal-ing pathways including NF-�B, c-Jun N-terminal kinase-1 (JNK1), ERK, and tissueinhibitors of metalloproteinases (TIMPs). TIMPs inhibit MMP-2-dependant cleav-age of pro-IL-1�. Astrocyte activation increases inter-astrocyte communication viaa calcium cascade through an astroglial network of gap-junctions and the productionof cytokines such as IL-1�, IL-6, and TNF-�; chemokines such as monocyte chemoat-tractant protein-1 (MCP-1), PGE2, NO, ATP (which binds to P2RX4), and glutamate(which acts on its synaptic homeostasis). d: neuronal expression of CCL2 promotesinfiltration by macrophages [27]. T cells also infiltrate the central nervous systemin response to chemotactic signals. Th1 cells promote pain sensitization, which isinhibited by Th2 cells [13]. Rapid accumulation of proinflammatory cytokines andchemokines in the dorsal root ganglion after nerve injury contributes to inducedirect sensitization of the sensory neurons. These cytokines and chemokines (aswell as PGE2, bradykinin, C5a, and C3a) produced by glial and immune cells interactwith their specific receptors on the ganglion neurons, thereby increasing the num-bns

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er and calcium conductance of the AMPA and NMDA receptors, which increaseseuronal excitability and synaptic transmission and amplifies the primary afferentignal sent to the dorsal horn.

athogens and can recognize, sequester, and process antigens andlay a role in local innate immune responses. TLR activation in

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he CNS modulates neuron-glial cell communication, producingn excitatory positive-feedback loop. TLR activation is pivotal inicroglial activation and the development of neuropathic pain. In

nockout mice for TLR2 or TLR4, decreases are seen in microglial

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activation and proinflammatory cytokine induction after periph-eral nerve injury, as well as in behaviors reflecting neuropathic pain[24]. Opioids can activate the glia via TLR4, inducing the release ofproinflammatory cytokines, which can cause tolerance and loss ofanalgesic efficacy, as well as dependency and adverse events suchas respiratory depression [21–25]. Many cytokines generate acti-vating signals from the neurons to the glia. Electrical stimulationof the sciatic nerve or dorsal root in rats induces the release ofthe chemokine CX3CL1 (fractalkine), increases microglial activa-tion (Iba1 immunolabeling) in the dorsal horn, and exacerbatessensitivity to pain. Fractalkine is a transmembrane glycoproteineexpressed on primary and dorsal horn sensory neurons. A solubledomain can be cleaved away by proteolysis, and both the trans-membrane and soluble forms are active. The fractalkine receptorCX3CR1 is expressed by glial cells. Fractalkine-mediated signalingbetween the neurons and glial cells may contribute to the devel-opment of neuropathic pain by producing responses mediated byIL-1� and IL-6 via microglial activation [26]. Binding to astrocyticCX3CR1 mediates the chronic stages of neuropathic pain. In knock-out mice for CCR2, mechanical hypersensitivity after partial sciaticnerve ligation is attenuated. Expression of the CCL2 receptor CCR2in the spinal cord induces infiltration by macrophages [27], whichdifferentiate gradually into glial cells. Microglial activation inducedby nerve injury is mediated by kinase-activating phosphorylation(MAP kinase p38, extracellular signal-related kinase [ERK]) [28].Neurons act also on central glial cells, which are activated by neu-rotransmitters and express the corresponding receptors [29]. Thus,neurons can interact with synaptic transmission.

Nerve injury also induces increased proliferation and activa-tion of the astrocytes in the ipsilateral spinal cord. Compared tothe microglial response, astrocyte proliferation occurs later and ata slower pace but is also longer lasting. Astrocytes are intimatelyassociated with neurons and can therefore regulate synaptic activ-ity by releasing neuromodulators such as glutamate, D-serine, andATP. Astrocytes express ionotropic receptors (NMDA-voltage-gatedcalcium channels – and non-NMDA) and metabotropic recep-tors (e.g., for glutamate, purines, and substance P) and releasecytokines, chemokines, and amino acids, thereby increasing dorsalhorn excitability and contributing to the development of chronicpain [30].

3.3. Central role for immune cells and cytokines

3.3.1. Chemotaxis, migration, and infiltration by immune cellsMicroglial recruitment and activation in the dorsal root

glanglion then in the dorsal horn is accompanied with upregu-lation of chemoattractant molecules and invasion by T cells andmacrophages traveling to the site of nerve injury via the blood-stream. The macrophages gradually undergo differentiation toa microglial phenotype. Macrophages, derived from circulatingmonocytes, and microglial cells, which represent resident phago-cytic mononuclear cells in the CNS, share many immunologicaland functional similarities. Macrophages, lymphocytes, and satel-lite microglial cells participate in neuroimmune activation of glialcells in the dorsal root ganglion then in the dorsal horn, promotingthe development of chronic neuropathic pain. The immune cellsinteract with the neurons and glial cells to produce neuroimmunesynapses. This infiltration of the CNS by immune cells is initiatedby chemotactic signals. Thus, C5a and CCL2 are upregulated in thespinal cord microglia after nerve injury [31]. Mice lacking CCR2are characterized by decreased recruitment of neutrophils and

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macrophages in the dorsal root ganglion and by absence of mechan-ical allodynia after sciatic nerve constriction [27]. Furthermore,dorsal horn infiltration by T cells and IFN�-mediated signaling con-tribute to the development of sensitization and neuropathic pain.

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Fig. 4. Neuroimmune regulation of proinflammatory cytokines (TNF-�, IL-6, IL-1�)in the central nervous system: a: TNF-�, via the signaling pathway that involvesTNF receptor 1 (TNFR1) and MAP kinase p38, increases the density of tetrodotoxin(TTX)-resistant sodium channels in the dorsal root ganglion nociceptors and canalso stimulate the transcriptionof the TRPV-1 gene encoding a calcium channelinvolved in propagating and extending painful hyperalgesia to the ipsilateral andcontralateral sides in the central nervous system. Spinal cord TNF-� spinal pro-motes infiltration by macrophages, activates the glia via MAP kinase p38, andacts directly on neurons via its membrane receptor to increase signaling throughcalcium-permeable AMPA channels via phosphorylation of their subunit Glu-A1and transport to the membrane of dorsal horn neurons [36]; a’: in the dorsal horn,release of substance P afferent C fibers followed by its interaction with the microglialNK1 receptor triggers a transcriptional mechanism that increases the expresison ofmicroglial membrane TNF-� without inducing expression of TNF-� cleaving enzyme(TACE), which cleaves membrane TNF-� to soluble TNF-�. The result is increasedmicroglial activation by cell-cell interactions. In contrast, microglial TLR4 stimula-tion induces the expression not only of membrane TNF-�, but also of TACE, resultingin the release of soluble TNF-� [35]; b: suppressor of cytokine signaling 3 (SOCS3) isa protein that prevents STAT3 phosphorylation, thereby inhibiting overexpressionof IL-6, CC chemokine ligand 2 (CCL2), and the transcription factor ATF3 in the spinalcord [32]; c: ATP induces IL-1� release by the microglia in spinal cord sections, via amechanism dependent on the P2RX7 purinoceptors and TLR4 [33]. IL-1� release isalso induced by the CX3CL1 (fractalkine) and MAPK p38 pathways. Pro-IL-1� cleav-amm

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ge to IL-1� by MMP-9 in the microglia and MMP-2 in the astrocytes contributes toaintain activation of these cells [34]; d: IL-18 serves as a messenger between theicroglia and astrocytes [38].

ice lacking T cells (or neutrophils) fail to develop neuropathicechanical hypersensitivity.

.3.2. Effects of cytokines and chemokines in the central nervousystem

Microglial MAP kinases can be activated by IL-1� and TNF-�,nducing, via transcription factors such as NF�B, additional produc-ion of IL-1�, TNF-�, IL-6, IL-10, TGF-�, PGE2, BDNF, and cathepsin

and promoting the deleterious effects of microglial infiltrationnd phagocytosis in neuropathic pain (Fig. 4). Blocking the sig-aling pathways mediated by IL-1� or IL-6 diminishes behaviorselated to neuropathic pain [8]. Furthermore, cytokines such aseukemia inhibitory factor (LIF) and IL-6 modulate the productionf peptide neurotransmitters, and proinflammatory cytokines pro-uced by the microglia interact with receptors for excitatory aminocids. The phenotypic changes in sensory neurons that result fromhe effects of these cytokines affect synaptic transmission towardhe spinal cord (neuroimmune spinal-cord plasticity responsibleor chronic pain). IL-6 induces early activation of the JAK/STAT3ignaling pathways in the spinal cord microglia, contributing toeuropathic pain development in a rat nerve-injury model [32].

L-1� has a pivotal effect on central pain integration via modula-ion of the microglia, astrocytes, and neurons. This cytokine also

Please cite this article in press as: Guillot X, et al. Pain and immunity.

lays a key role as a messenger between neurons and glial cells33,34]. TNF-� is produced by immune and glial cells after nervenjury and contributes to their activation and to the stimulation ofeuronal ion channels [35,36]. TNF-� antagonist therapy in patients

PRESSine xxx (2011) xxx–xxx 7

with rheumatoid arthritis is followed within 24 hours by nocicep-tive activity blockade in the thalamus, somatosensory cortex, andlimbic system, as documented by blood-oxygen level-dependent(BOLD) functional magnetic resonance imaging. This central effectantedates the blockade of joint and systemic inflammation and mayexplain the often strikingly short delay of action of TNF-� antag-onists. Thus, TNF-�, in addition to its role as a proinflammatorycytokine, is also involved in central pain integration in rheumatoidarthritis [37]. After spinal nerve injury, the microglia shows upreg-ulation of IL-18 and of its receptor, located specifically at the surfaceof the spinal-cord astrocytes. The result is activation of the NF-�Bpathway in the astrocytes and the development of neuropathic painbehaviors in rats [38].

4. Future prospects and treatment targets

Most analgesics are inadequately effective on neuropathicpain and induce unwanted effects. The current treatment strate-gies involve diminishing the excitability of peripheral or centralneurons by modulating ion channel activity or replicating an ampli-fied endogenous inhibitory mechanism. Insights into interactionsbetween the nervous system components (most notably the glialcells) and the immune microenvironment in neuropathic pain mayopen up possibilities for improved treatment targeting. Preclini-cal studies, usually done in murine models, have evaluated severalimmune system and glial modulation pathways and require vali-dation in humans.

4.1. Stimulation of neuroimmune antiinflammatory andanalgesic pathways (Table 1)

After an injury, the immune cells also release factors thatpromote tissue repair, suppress inflammation, and diminish pain(counterregulatory mechanisms). Stimulation of these pathwaysmay be more effective than suppression of the proinflammatorypathways, which often also exert protective and reparative effects.Potential targets include the production of endogenous opioids [39]and antiinflammatory cytokines (IL-10 and IL-4) [40], the cannabi-noid receptors CB1 and CB2 [41], purinoceptors [42], modulationof the glial cell phagocytic properties [21–32], and astrocytic glu-tamate transporters [30].

Resolution of the inflammatory process is an active phe-nomenon that allows a return to homeostasis. Inflammationresolution involves several lipid mediators, including the resolvins.Cyclooxygenase inhibitors compromise the resolution of inflam-mation, which requires functional cyclooxygenase [43,44].

4.2. Inhibition of proinflammatory and algogenic neuroimmunepathways (Table 2)

The main objective is to inhibit glial activation, which is respon-sible for the transition to chronic pain (inhibition of TLR4 [23–25],of purinoceptors [42,45–47], and of enzymes required for glialmetabolism [48–50]). Inhibition of glial MAP kinases seems promis-ing [21,28,51] but may produce broader cellular effects. Targetedblockade of proinflammatory cytokines (IL-15 [52], IL-6, TNF-� [53], IL-1� [54–56]), C5a receptor [11,57], NGF [58–60], andneuronal TRP calcium channels [18] may also hold therapeuticpotential.

Joint Bone Spine (2011), doi:10.1016/j.jbspin.2011.10.008

5. Conclusion

Neuropathic pain exhibits the characteristics of an abnor-mal neuroimmune process involving reciprocal communication

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etween immune cells, glial cells, and neurons to modify pain sen-itivity and to mediate the transition from acute to chronic pain.

The glial cells are at the crossroads between the immune systemnd the nervous system and play a central role in pain integrationnd sensitization, most notably via their effects as cells of the innatemmune system. The role for adaptive immunity in these phenom-na is less well understood. In addition, limitations to currentlyvailable animal models include brief duration of acute inflamma-ory response and hyperalgesia, which decline over time and areonsequently less than ideal for investigating the role played bymmune cells in chronic pain.

The ability to differentiate the beneficial (adaptive) effects fromhe toxic (nonadaptive) effects of immune and glial responses toerve injury will be crucial to the development of targeted (ago-istic or antagonistic) treatment strategies for neuropathic pain.

isclosure of interest

The authors declare that they have no conflicts of interest con-erning this article.

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