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Research ArticleNeuropharmacology

Epigenetic Augmentation of the Macrophage Inflammatory Protein 2/C-X-C Chemokine Receptor Type 2 Axis through Histone H3 Acetylation in Injured Peripheral Nerves Elicits Neuropathic Pain

Norikazu Kiguchi, Yuka Kobayashi, Takehiko Maeda, Yohji Fukazawa, Kazuo Tohya, Michio Kimura and Shiroh Kishioka
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 577-587; DOI: https://doi.org/10.1124/jpet.111.187724
Norikazu Kiguchi
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Yuka Kobayashi
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Takehiko Maeda
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Yohji Fukazawa
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Kazuo Tohya
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Michio Kimura
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Shiroh Kishioka
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Abstract

Although there is growing evidence showing that the involvement of chemokines in the pathogenesis of neuropathic pain is associated with neuroinflammation, the details are unclear. We investigated the C-X-C chemokine ligand type 2 [macrophage inflammatory protein 2 (MIP-2)]/C-X-C chemokine receptor type 2 (CXCR2) axis and epigenetic regulation of these molecules in neuropathic pain after peripheral nerve injury. Expression of MIP-2 and CXCR2 were up-regulated and localized on accumulated neutrophils and macrophages in the injured sciatic nerve (SCN) after partial sciatic nerve ligation (PSL). Perineural injection of MIP-2-neutralizing antibody (anti-MIP-2) or the CXCR2 antagonist N-(2-bromophenyl)-N′-(2-hydroxy-4-nitrophenyl)urea (SB225002) prevented PSL-induced tactile allodynia and thermal hyperalgesia. Perineural injection of recombinant MIP-2 elicited neuropathic pain-like behaviors. Anti-MIP-2 suppressed neutrophil accumulation in the SCN after PSL. Neutrophil depletion by intraperitoneal injection of Ly6G antibody attenuated PSL-induced neuropathic pain. Both anti-MIP-2 and SB225002 suppressed up-regulation of inflammatory cytokines and chemokines in the injured SCN. In addition, acetylation of histone H3 [lysine (Lys9)-acetylated histone H3 (AcK9-H3)] on the promoter region of MIP-2 and CXCR2 was increased in the injured SCN after PSL. Expression of AcK9-H3 was observed in the nuclei of neutrophils and macrophages surrounding the epineurium. Administration of the histone acetyltransferase inhibitor anacardic acid suppressed the up-regulation of MIP-2 and CXCR2 in the SCN after PSL and resulted in the prevention of PSL-induced neuropathic pain. Taken together, these results show that augmentation of the MIP-2/CXCR2 axis by hyperacetylation of histone H3 on the promoter region of MIP-2 and CXCR2 located in the injured peripheral nerve elicits chronic neuroinflammation through neutrophil accumulation, leading to neuropathic pain.

Footnotes

  • This work was supported by a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science, and Technology [Grant B:21791469]; and a grant from the Smoking Research Foundation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187724.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    IL
    interleukin
    TNF
    tumor necrosis factor
    CXCR2
    C-X-C chemokine receptor type 2
    CXCL2
    C-X-C chemokine ligand type 2
    MIP
    macrophage inflammatory protein
    rMIP-2
    recombinant mouse MIP-2
    PSL
    partial sciatic nerve ligation
    SCN
    sciatic nerve
    HAT
    histone acetyltransferase
    ACA
    anacardic acid
    IP
    immunoprecipitation
    ChIP
    chromatin IP
    MPO
    myeloperoxidase
    AcK9-H3
    lysine (Lys9)-acetylated histone H3
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    qPCR
    quantitative PCR
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    Veh
    vehicle
    SB225002
    N-(2-bromophenyl)-N′-(2-hydroxy-4-nitrophenyl)urea
    PBS
    phosphate-buffered saline
    BSA
    bovine serum albumin
    RIPA
    radioimmunoprecipitation assay
    Ab
    antibody.

  • Received September 6, 2011.
  • Accepted November 30, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleNeuropharmacology

Peripheral MIP-2/CXCR2 Axis Elicits Neuropathic Pain

Norikazu Kiguchi, Yuka Kobayashi, Takehiko Maeda, Yohji Fukazawa, Kazuo Tohya, Michio Kimura and Shiroh Kishioka
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 577-587; DOI: https://doi.org/10.1124/jpet.111.187724

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Research ArticleNeuropharmacology

Peripheral MIP-2/CXCR2 Axis Elicits Neuropathic Pain

Norikazu Kiguchi, Yuka Kobayashi, Takehiko Maeda, Yohji Fukazawa, Kazuo Tohya, Michio Kimura and Shiroh Kishioka
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 577-587; DOI: https://doi.org/10.1124/jpet.111.187724
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