Neuronal CCL21 Up-regulates Microglia P2X4 Expression and Initiates Neuropathic Pain Development

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2011 Mar 29

PMID 21441897

Citations 78

Authors

Knut Biber

Makoto Tsuda

Hidetoshi Tozaki-Saitoh

Keiko Tsukamoto

Emika Toyomitsu

Takahiro Masuda

Hendrikus Boddeke

Kazuhide Inoue

Affiliations

Soon will be listed here.

Abstract

Up-regulation of P2X4 receptors in spinal cord microglia is crucial for tactile allodynia, an untreatable pathological pain reaction occurring after peripheral nerve injury. How nerve injury in the periphery leads to this microglia reaction in the dorsal horn of the spinal cord is not yet understood. It is shown here that CCL21 was rapidly expressed in injured small-sized primary sensory neurons and transported to their central terminals in the dorsal horn. Intrathecal administration of a CCL21-blocking antibody diminished tactile allodynia development in wild-type animals. Mice deficient for CCL21 did not develop any signs of tactile allodynia and failed to up-regulate microglial P2X4 receptor expression. Microglia P2X4 expression was enhanced by CCL21 application in vitro and in vivo. A single intrathecal injection of CCL21 to nerve-injured CCL21-deficient mice induced long-lasting allodynia that was undistinguishable from the wild-type response. This effect of CCL21 injection was strictly dependent on P2X4 receptor function. Since neuronal CCL21 is the earliest yet identified factor in the cascade leading to tactile allodynia, these findings may lead to a preventive therapy in neuropathic pain.

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References

Kim S, Chung J . An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992; 50(3):355-363. DOI: 10.1016/0304-3959(92)90041-9. View

Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter M . P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003; 424(6950):778-83. DOI: 10.1038/nature01786. View

Ransohoff R, Perry V . Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009; 27:119-45. DOI: 10.1146/annurev.immunol.021908.132528. View

Tsuda M, Tozaki-Saitoh H, Masuda T, Toyomitsu E, Tezuka T, Yamamoto T . Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia. 2007; 56(1):50-8. DOI: 10.1002/glia.20591. View

Tsuda M, Ishii S, Masuda T, Hasegawa S, Nakamura K, Nagata K . Reduced pain behaviors and extracellular signal-related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet-activating factor receptor. J Neurochem. 2007; 102(5):1658-1668. DOI: 10.1111/j.1471-4159.2007.04796.x. View

Biber K, Neumann H, Inoue K, Boddeke H . Neuronal 'On' and 'Off' signals control microglia. Trends Neurosci. 2007; 30(11):596-602. DOI: 10.1016/j.tins.2007.08.007. View

Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H . The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior. Neuroscience. 2005; 137(3):961-70. DOI: 10.1016/j.neuroscience.2005.10.015. View

Haynes S, Hollopeter G, Yang G, Kurpius D, Dailey M, Gan W . The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006; 9(12):1512-9. DOI: 10.1038/nn1805. View

Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K . IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci U S A. 2009; 106(19):8032-7. PMC: 2683100. DOI: 10.1073/pnas.0810420106. View

10.

Tsuda M, Toyomitsu E, Komatsu T, Masuda T, Kunifusa E, Nasu-Tada K . Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia. 2008; 56(5):579-85. DOI: 10.1002/glia.20641. View

11.

Tsuda M, Kohro Y, Yano T, Tsujikawa T, Kitano J, Tozaki-Saitoh H . JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011; 134(Pt 4):1127-39. PMC: 4571138. DOI: 10.1093/brain/awr025. View

12.

Lashbrook J, Ossipov M, Hunter J, Raffa R, Tallarida R, Porreca F . Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX1- and COX2-inhibitors in nerve-injured rats. Pain. 1999; 82(1):65-72. DOI: 10.1016/S0304-3959(99)00031-7. View

13.

de Jong E, Dijkstra I, Hensens M, Brouwer N, van Amerongen M, Liem R . Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. J Neurosci. 2005; 25(33):7548-57. PMC: 6725403. DOI: 10.1523/JNEUROSCI.1019-05.2005. View

14.

Rappert A, Bechmann I, Pivneva T, Mahlo J, Biber K, Nolte C . CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J Neurosci. 2004; 24(39):8500-9. PMC: 6729901. DOI: 10.1523/JNEUROSCI.2451-04.2004. View

15.

Obata K, Katsura H, Sakurai J, Kobayashi K, Yamanaka H, Dai Y . Suppression of the p75 neurotrophin receptor in uninjured sensory neurons reduces neuropathic pain after nerve injury. J Neurosci. 2006; 26(46):11974-86. PMC: 6674869. DOI: 10.1523/JNEUROSCI.3188-06.2006. View

16.

Colburn R, Rickman A, DeLeo J . The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol. 1999; 157(2):289-304. DOI: 10.1006/exnr.1999.7065. View

17.

Hanisch U, Kettenmann H . Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10(11):1387-94. DOI: 10.1038/nn1997. View

18.

Campbell J, Meyer R . Mechanisms of neuropathic pain. Neuron. 2006; 52(1):77-92. PMC: 1810425. DOI: 10.1016/j.neuron.2006.09.021. View

19.

Miller R, Rostene W, Apartis E, Banisadr G, Biber K, Milligan E . Chemokine action in the nervous system. J Neurosci. 2008; 28(46):11792-5. PMC: 2746239. DOI: 10.1523/JNEUROSCI.3588-08.2008. View

20.

Chaplan S, Bach F, Pogrel J, Chung J, Yaksh T . Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994; 53(1):55-63. DOI: 10.1016/0165-0270(94)90144-9. View