著者
木口 倫一 岸岡 史郎
出版者
日本疼痛学会
雑誌
PAIN RESEARCH (ISSN:09158588)
巻号頁・発行日
vol.29, no.1, pp.9-16, 2014-03-10 (Released:2014-03-29)
参考文献数
21

Recently, the involvement of inflammatory mediators such as chemokines in neuropathic pain has been focused. Among inflammatory cells recruited into the injured peripheral nerves, macrophages play key roles in chronic neuroinflammation through cytokine–chemokine network. As epigenetic histone modifications induce long–lasting expression of inflammatory mediators, we highlight the contribution of histone modifications in the injured peripheral nerves to neuropathic pain.   After partial sciatic nerve ligation (PSL) in mice, F4⁄80+ macrophages were accumulated in the injured sciatic nerve (SCN). By microarray analysis, several inflammatory chemokine ligands and those receptors were upregulated in the injured SCN on day 7 after PSL. Indeed, the expression levels of CC–chemokine ligand (CCL) 3 and CCL8 showed the highest upregulation, and were confirmed by quantitative RT–PCR. Moreover, those receptors including CCR1, CCR2 and CCR5 were markedly upregulated after PSL. Chromatin precipitation assay revealed the acetylation in K9 residue (H3K9Ac) and trimethylation in K4 residue (H3K4me3) of histone H3, facilitating gene transcriptions associated with chromatin remodeling, on the promoter regions of CCLs in the injured SCN. By immunohistochemistry, upregulated CCL3 or CCL8 was located on the accumulated F4⁄80+ macrophages. Expressions of H3K9Ac and H3K4me3 were also increased in the injured SCN, and those were detected in the nuclei of macrophages expressing CCLs.   These findings indicate that facilitation of chemokine signaling through histone H3 modifications in macrophages largely contributes to peripheral neuroinflammation leading to neuropathic pain. Further research considering the critical components of peripheral neuroinflammation exploit novel therapeutic strategy of neuropathic pain.

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