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Licensed Unlicensed Requires Authentication Published by De Gruyter November 14, 2019

Role of the immune system in neuropathic pain

Marzia Malcangio

Abstract

Background

Acute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).

Critical role for immune system cells in chronic pain

Preclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.

Immune system reactions to peripheral nerve injuries

At the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.

Immune system mechanisms in the central nervous system

In the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.

Conclusions and implications

Definition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

  1. Author’s statements

  2. Research funding: Current work In MM lab is supported by the Medical Research Council UK (MR/M023893/1 and MR/T002883/1), Versus Arthritis (grant 21961); European Union’s Horizon 2020 research and innovation programme “TOBeATPAIN” under the Marie Skłodowska-Curie grant agreement No 764860.

  3. Conflicts of interest: The author declares no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

[1] Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe; prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287–333.10.1016/j.ejpain.2005.06.009Search in Google Scholar

[2] Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1–32.10.1146/annurev.neuro.051508.135531Search in Google Scholar

[3] Malcangio M. Microglia and chronic pain. Pain 2016;157:1002–3.10.1097/j.pain.0000000000000509Search in Google Scholar

[4] Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain 2013;154:S10–28.10.1016/j.pain.2013.06.022Search in Google Scholar

[5] Austin PJ, Moalem-Taylor G. The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol 2010;229:26–50.10.1016/j.jneuroim.2010.08.013Search in Google Scholar

[6] Xanthos DN, Sandkuhler J. Neurogenic inflammation:inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 2015;15:43–53.10.1038/nrn3617Search in Google Scholar

[7] Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science 2016;354:527–77.10.1126/science.aaf8924Search in Google Scholar

[8] Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M. Role of spinal microglia in rat models of periheral injury and inflammation. Eur J Pain 2007;11:223–30.10.1016/j.ejpain.2006.02.003Search in Google Scholar

[9] Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K. P2X4 receptors induced in spinal micoglia gate tactile allodynia after injury. Nature 2003;424:778–83.10.1038/nature01786Search in Google Scholar

[10] Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neruopathci pain. Nature 2005;438:1017–21.10.1038/nature04223Search in Google Scholar

[11] Gagnon M, Bergeron MJ, Lavertu G, Castonguay A, Tripathy S, Bonin RP, Perez-Sanchez J, Boudreau D, Wang B, Dumas L, Valade I, Bachand K, Jacob-Wagner M, Tardif C, Kianicka I, Isenring P, Attardo G, Coull JA, De Koninck Y. Chloride extrusion enhancers as novel therpeutics fro neruological diseases. Nat Med 2013;19:1524–8.10.1038/nm.3356Search in Google Scholar

[12] Matsumura Y, Yamashita T, Sasaki A, Nakata E, Kohno K, Masuda T, Tozaki-Saitoh H, Imai T, Kuraishi Y, Tsuda M, Inoue K. A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain. Sci Rep 2016;6:32461.10.1038/srep32461Search in Google Scholar

[13] Williams WA, Linley JE, Jones CA, Shibata Y, Snijder A, Button J, Hatcher JP, Huang L, Taddese B, Thornton P, Schofield DJ, Thom G, Popovic B, Dosanjh B, Wilkinson T, Hughes J, Dobson CL, Groves MA, Webster CI, Billinton A, et al. Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain. Pain 2019;160:1989–2003.10.1097/j.pain.0000000000001587Search in Google Scholar

[14] Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, Martin LJ, Austin JS, Sotocinal SG, Chen D, Yang M, Shi XQ, Huang H, Pillon NJ, Bilan PJ, Tu Y, Klip A, Ji RR, Zhang J, Salter MW, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci 2015;18:1081–3.10.1038/nn.4053Search in Google Scholar

[15] Masuda T, Ozono Y, Mikuriya S, Kohro Y, Tozaki-Saitoh H, Iwatsuki K, Uneyama H, Ichikawa R, Salter MW, Tsuda M, Inoue K. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun 2016;7:12529.10.1038/ncomms12529Search in Google Scholar

[16] Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, Evans-Reinsch Z, Braz J, Devor M, Abboud-Werner SL, Lanier LL, Lomvardas S, Basbaum AI. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat Neurosci 2016;19:94–101.10.1038/nn.4189Search in Google Scholar

[17] Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci USA 2007;104:10655–60.10.1073/pnas.0610811104Search in Google Scholar

[18] Clark AK, Yip PK, Malcangio M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J Neurosci 2009;29:6945–54.10.1523/JNEUROSCI.0828-09.2009Search in Google Scholar

[19] Clark AK, Wodarski R, Guida F, Sasso O, Malcangio M. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 2010;58:1710–26.10.1002/glia.21042Search in Google Scholar

[20] Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 2007;21:642–51.10.1016/j.bbi.2006.11.003Search in Google Scholar

[21] Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, Ren Y, DiCicco-Bloom E, Young W, Dong H, Wu LJ. Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep 2016;16:605–14.10.1016/j.celrep.2016.06.018Search in Google Scholar

[22] Hewitt E, Pitcher T, Rizoska B, Tunblad K, Henderson I, Sahlberg BL, Grabowska U, Classon B, Edenius C, Malcangio M, Lindström E. Selective Cathepsin S inhibition with MIV-247 attenuates mechanical allodynia and enhances the antiallodynic effects of gabapentin and pregabalin in a mouse model of neuropathic pain. J Pharmacol Exp Ther 2016;358:387–96.10.1124/jpet.116.232926Search in Google Scholar

[23] Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN. Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 2005;114:386–96.10.1016/j.pain.2005.01.002Search in Google Scholar

[24] Clark AK, Gruber-Schoffnegger D, Drdla-Schutting R, Gerhold KJ, Malcangio M, Sandkühler J. Selective activation of microglia facilitates synaptic strength. J Neurosci 2015;35:4552–70.10.1523/JNEUROSCI.2061-14.2015Search in Google Scholar

[25] Zhou LJ, Peng J, Xu YN, Zeng WJ, Zhang J, Wei X, Mai CL, Lin ZJ, Liu Y, Murugan M, Eyo UB, Umpierre AD, Xin WJ, Chen T, Li M, Wang H, Richardson JR, Tan Z, Liu XG, Wu LJ. Microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep 2019;27:3844–59.10.1016/j.celrep.2019.05.087Search in Google Scholar

[26] Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji RR, Riley M, Wasan AD, Zürcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, Hooker JM. Evidence for brain glial activation in chronic pain patients. Brain 2015;138:604–15.10.1093/brain/awu377Search in Google Scholar

[27] Albrecht DS, Forsberg A, Sandström A, Bergan C, Kadetoff D, Protsenko E, Lampa J, Lee YC, Höglund CO, Catana C, Cervenka S, Akeju O, Lekander M, Cohen G, Halldin C, Taylor N, Kim M, Hooker JM, Edwards RR, Napadow V, et al. Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. Brain Beh Immun 2019;75:72–83.10.1016/j.bbi.2018.09.018Search in Google Scholar

[28] Bäckryd E, Tanum L, Lind AL, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res 2017;10:515–25.10.2147/JPR.S128508Search in Google Scholar

[29] Sisignano M, Baron R, Scholich K, Geisslinger G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol 2014;10:694–707.10.1038/nrneurol.2014.211Search in Google Scholar

[30] Old EA, Nadkarni S, Grist J, Gentry C, Bevan S, Kim KW, Mogg AJ, Perretti M, Malcangio M. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest 2014;124:2023–36.10.1172/JCI71389Search in Google Scholar

[31] Montague K, Simeoli R, Valente J, Malcangio M. A novel interaction between CX3CR1 and CCR2 signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain. J Neuroinflammation 2018;15:101.10.1186/s12974-018-1116-6Search in Google Scholar

[32] Adilakshmi T, Sudol I, Tapinos N. Combinatorial action of miRNAs regulates transcriptional and post-transcriptional gene silencing following in vivo PNS injury. PLoS one 2012;7:e39674.10.1371/journal.pone.0039674Search in Google Scholar

[33] Kress M, Hüttenhofer A, Landry M, Kuner R, Favereaux A, Greenberg D, Bednarik J, Heppenstall P, Kronenberg F, Malcangio M, Rittner H, Uçeyler N, Trajanoski Z, Mouritzen P, Birklein F, Sommer C, Soreq H. MicroRNAs in nociceptive circuits as predictors of future clinical applications. Front Mol Neurosci 2013;6:33.10.3389/fnmol.2013.00033Search in Google Scholar

[34] Bali KK, Selvaraj D, Satagopam VP, Lu J, Schneider R, Kuner R. Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain. EMBO Mol Med 2013;5:1740–58.10.1002/emmm.201302797Search in Google Scholar

[35] Niederberger E, Kynast K, Lotsch J, Geisslinger G. MicroRNAs as new players in the pain game. Pain 2011;152:1455–8.10.1016/j.pain.2011.01.042Search in Google Scholar

[36] Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, Ji RR. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 2014;82:47–54.10.1016/j.neuron.2014.02.011Search in Google Scholar

[37] Zhang ZJ, Guo JS, Li SS, Wu XB, Cao DL, Jiang BC, Jing PB, Bai XQ, Li CH, Wu ZH, Lu Y, Gao YJ. TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. J Exp Med 2018;215:3019–37.10.1084/jem.20180800Search in Google Scholar

[38] Strickland IT, Richards L, Holmes FE, Wynick D, Uney JB, and Wong LF. Axotomy-induced miR-21 promotes axon growth in adult dorsal root ganglion neurons. PLoS One 2011;6:e23423.10.1371/journal.pone.0023423Search in Google Scholar

[39] Simeoli R, Montague K, Jones HR, Castaldi L, Chambers D, Kelleher JH, Vacca V, Pitcher T, Grist J, Al-Ahdal H, Wong LF, Perretti M, Lai J, Mouritzen P, Heppenstall P, Malcangio M. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat Commun 2017;8:1778.10.1038/s41467-017-01841-5Search in Google Scholar

[40] Smith JB, Agarwall P, Bhowmick NA. MicroRNA applications for prostate, ovarian and breast cancer in the era of precision medicine. Endocrine-Related Cancer 2017;24:R157–72.10.1530/ERC-16-0525Search in Google Scholar

Received: 2019-10-21
Accepted: 2019-10-22
Published Online: 2019-11-14
Published in Print: 2019-12-18

©2020 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.

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