Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain

Satoshi Imai, Minoru Narita, Daigo Ikegami, Akira Yamashita, Toshikazu Shimizu, Michiko Narita, Keiichi Niikura, Masaharu Furuya, Yasuhisa Kobayashi, Kazuhiko Miyashita, Daiki Okutsu, Akira Kato, Atsushi Nakamura, Akiko Araki, Kazuo Omi, Masaya Nakamura, Hirotaka James Okano, Hideyuki Okano, Takayuki Ando, Hideyuki TakeshimaToshikazu Ushijima, Naoko Kuzumaki, Tsutomu Suzuki

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

A multiplex analysis for profiling the expression of candidate genes along with epigenetic modification may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we found that partial sciatic nerve ligation most remarkably increased the expression of monocyte chemotactic protein 3 (MCP-3, known as CCL7) a total of 33 541 genes in the spinal cord, which lasted for 4 weeks. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at Lys27 at the MCP-3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin 6 knockout mice with partial sciatic nerve ligation. Consistent with these findings, a single intrathecal injection of recombinant proteins of interleukin 6 significantly increased MCP-3 messenger RNA with a decrease in the level of Lys27 trimethylation of histone H3 at the MCP-3 promoter in the spinal cord of mice. Furthermore, deletion of the C-C chemokine receptor type 2 (CCR2) gene, which encodes a receptor for MCP-3, failed to affect the acceleration of MCP-3 expression in the spinal cord after partial sciatic nerve ligation. A robust increase in MCP-3 protein, which lasted for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with partial sciatic nerve ligation was seen mostly in astrocytes, but not microglia or neurons. On the other hand, the increases in both microglia and astrocytes in the spinal cord by partial sciatic nerve ligation were mostly abolished in interleukin 6 knockout mice. Moreover, this increase in microglia was almost abolished by CCR2 gene deletion, whereas the increase in astrocytes was not affected in nerve-ligated mice that lacked the CCR2 gene. We also found that either in vivo or in vitro treatment with MCP-3 caused robust microglia activation. Under these conditions, intrathecal administration of MCP-3 antibody suppressed the increase in microglia within the mouse spinal cord and neuropathic pain-like behaviours after nerve injury. With the use of a functional magnetic resonance imaging analysis, we demonstrated that a single intrathecal injection of MCP-3 induced dramatic increases in signal intensity in pain-related brain regions. These findings suggest that increased MCP-3 expression associated with interleukin 6 dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia interaction in the spinal cord and could play a critical role in the neuropathic pain-like state.

Original languageEnglish
Pages (from-to)828-843
Number of pages16
JournalBrain
Volume136
Issue number3
DOIs
Publication statusPublished - 2013 Mar

Fingerprint

Chemokine CCL7
Neuralgia
Epigenomics
Microglia
Transcriptional Activation
Spinal Cord
Sciatic Nerve
Astrocytes
Ligation
Chemokine Receptors
Interleukin-6
C Chemokines
Spinal Injections
Knockout Mice
Histones
Genes
CC Chemokines
Gene Deletion
Wounds and Injuries
Gene Expression Profiling

Keywords

  • chemokines
  • microglia
  • nerve injury
  • neuropathic pain
  • spinal cord plasticity

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Imai, S., Narita, M., Ikegami, D., Yamashita, A., Shimizu, T., Narita, M., ... Suzuki, T. (2013). Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain, 136(3), 828-843. https://doi.org/10.1093/brain/aws330

Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. / Imai, Satoshi; Narita, Minoru; Ikegami, Daigo; Yamashita, Akira; Shimizu, Toshikazu; Narita, Michiko; Niikura, Keiichi; Furuya, Masaharu; Kobayashi, Yasuhisa; Miyashita, Kazuhiko; Okutsu, Daiki; Kato, Akira; Nakamura, Atsushi; Araki, Akiko; Omi, Kazuo; Nakamura, Masaya; James Okano, Hirotaka; Okano, Hideyuki; Ando, Takayuki; Takeshima, Hideyuki; Ushijima, Toshikazu; Kuzumaki, Naoko; Suzuki, Tsutomu.

In: Brain, Vol. 136, No. 3, 03.2013, p. 828-843.

Research output: Contribution to journalArticle

Imai, S, Narita, M, Ikegami, D, Yamashita, A, Shimizu, T, Narita, M, Niikura, K, Furuya, M, Kobayashi, Y, Miyashita, K, Okutsu, D, Kato, A, Nakamura, A, Araki, A, Omi, K, Nakamura, M, James Okano, H, Okano, H, Ando, T, Takeshima, H, Ushijima, T, Kuzumaki, N & Suzuki, T 2013, 'Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain', Brain, vol. 136, no. 3, pp. 828-843. https://doi.org/10.1093/brain/aws330
Imai, Satoshi ; Narita, Minoru ; Ikegami, Daigo ; Yamashita, Akira ; Shimizu, Toshikazu ; Narita, Michiko ; Niikura, Keiichi ; Furuya, Masaharu ; Kobayashi, Yasuhisa ; Miyashita, Kazuhiko ; Okutsu, Daiki ; Kato, Akira ; Nakamura, Atsushi ; Araki, Akiko ; Omi, Kazuo ; Nakamura, Masaya ; James Okano, Hirotaka ; Okano, Hideyuki ; Ando, Takayuki ; Takeshima, Hideyuki ; Ushijima, Toshikazu ; Kuzumaki, Naoko ; Suzuki, Tsutomu. / Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. In: Brain. 2013 ; Vol. 136, No. 3. pp. 828-843.
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AU - Imai, Satoshi

AU - Narita, Minoru

AU - Ikegami, Daigo

AU - Yamashita, Akira

AU - Shimizu, Toshikazu

AU - Narita, Michiko

AU - Niikura, Keiichi

AU - Furuya, Masaharu

AU - Kobayashi, Yasuhisa

AU - Miyashita, Kazuhiko

AU - Okutsu, Daiki

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AU - Nakamura, Atsushi

AU - Araki, Akiko

AU - Omi, Kazuo

AU - Nakamura, Masaya

AU - James Okano, Hirotaka

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AU - Ando, Takayuki

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N2 - A multiplex analysis for profiling the expression of candidate genes along with epigenetic modification may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we found that partial sciatic nerve ligation most remarkably increased the expression of monocyte chemotactic protein 3 (MCP-3, known as CCL7) a total of 33 541 genes in the spinal cord, which lasted for 4 weeks. This increase in MCP-3 gene transcription was accompanied by the decreased trimethylation of histone H3 at Lys27 at the MCP-3 promoter. The increased MCP-3 expression associated with its epigenetic modification observed in the spinal cord was almost abolished in interleukin 6 knockout mice with partial sciatic nerve ligation. Consistent with these findings, a single intrathecal injection of recombinant proteins of interleukin 6 significantly increased MCP-3 messenger RNA with a decrease in the level of Lys27 trimethylation of histone H3 at the MCP-3 promoter in the spinal cord of mice. Furthermore, deletion of the C-C chemokine receptor type 2 (CCR2) gene, which encodes a receptor for MCP-3, failed to affect the acceleration of MCP-3 expression in the spinal cord after partial sciatic nerve ligation. A robust increase in MCP-3 protein, which lasted for up to 2 weeks after surgery, in the dorsal horn of the spinal cord of mice with partial sciatic nerve ligation was seen mostly in astrocytes, but not microglia or neurons. On the other hand, the increases in both microglia and astrocytes in the spinal cord by partial sciatic nerve ligation were mostly abolished in interleukin 6 knockout mice. Moreover, this increase in microglia was almost abolished by CCR2 gene deletion, whereas the increase in astrocytes was not affected in nerve-ligated mice that lacked the CCR2 gene. We also found that either in vivo or in vitro treatment with MCP-3 caused robust microglia activation. Under these conditions, intrathecal administration of MCP-3 antibody suppressed the increase in microglia within the mouse spinal cord and neuropathic pain-like behaviours after nerve injury. With the use of a functional magnetic resonance imaging analysis, we demonstrated that a single intrathecal injection of MCP-3 induced dramatic increases in signal intensity in pain-related brain regions. These findings suggest that increased MCP-3 expression associated with interleukin 6 dependent epigenetic modification at the MCP-3 promoter after nerve injury, mostly in spinal astrocytes, may serve to facilitate astrocyte-microglia interaction in the spinal cord and could play a critical role in the neuropathic pain-like state.

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