在小鼠切口性超敏反应中脊髓 CXCR2 信号的表观遗传调控。

Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice.

机构信息

* Postdoctoral Fellow, † Research Associate, ‡ Senior Research Scientist, # Professor, Department of Anesthesiology, Stanford University School of Medicine, Stanford, California, and Department of Anesthesiology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. § Senior Research Scientist, ‖ Research Assistant, Department of Anesthesiology, Stanford University School of Medicine. Received from the Anesthesia and Perioperative Medicine Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. Submitted for publication February 19, 2013. Accepted for publication May 17, 2013. The work was supported by NIH award GM079126 (Bethesda, Maryland) and VA Merit Review award 5I01BX000881 (Washington, D.C.). The authors declare no competing interests. Some findings included in this article were presented in abstract form at the annual meeting of the Society for Neuroscience, October 13-17, 2012, New Orleans, Louisiana.

出版信息

Anesthesiology. 2013 Nov;119(5):1198-208. doi: 10.1097/ALN.0b013e31829ce340.

DOI:10.1097/ALN.0b013e31829ce340

PMID:23756451

Abstract

BACKGROUND

The regulation of gene expression in nociceptive pathways contributes to the induction and maintenance of pain sensitization. Histone acetylation is a key epigenetic mechanism controlling chromatin structure and gene expression. Chemokine CC motif receptor 2 (CXCR2) is a proinflammatory receptor implicated in neuropathic and inflammatory pain and is known to be regulated by histone acetylation in some settings. The authors sought to investigate the role of histone acetylation on spinal CXCR2 signaling after incision.

METHODS

Groups of 5-8 mice underwent hind paw incision. Suberoylanilide hydroxamic acid and anacardic acid were used to inhibit histone deacetylase and histone acetyltransferase, respectively. Behavioral measures of thermal and mechanical sensitization as well as hyperalgesic priming were used. Both message RNA quantification and chromatin immunoprecipitation analysis were used to study the regulation of CXCR2 and ligand expression. Finally, the selective CXCR2 antagonist SB225002 was administered intrathecally to reveal the function of spinal CXCR2 receptors after hind paw incision.

RESULTS

Suberoylanilide hydroxamic acid significantly exacerbated mechanical sensitization after incision. Conversely, anacardic acid reduced incisional sensitization and also attenuated incision-induced hyperalgesic priming. Overall, acetylated histone H3 at lysine 9 was increased in spinal cord tissues after incision, and enhanced association of acetylated histone H3 at lysine 9 with the promoter regions of CXCR2 and keratinocyte-derived chemokine (CXCL1) was observed as well. Blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision.

CONCLUSIONS

Histone modification is an important epigenetic mechanism regulating incision-induced nociceptive sensitization. The spinal CXCR2 signaling pathway is one epigenetically regulated pathway controlling early and latent sensitization after incision.

摘要

背景

伤害性通路中基因表达的调控有助于痛觉敏化的诱导和维持。组蛋白乙酰化是一种关键的表观遗传机制，控制染色质结构和基因表达。趋化因子 CC 基元受体 2（CXCR2）是一种促炎性受体，参与神经病理性和炎性疼痛，并且已知在某些情况下受组蛋白乙酰化调节。作者试图研究在切口后脊髓 CXCR2 信号传导中组蛋白乙酰化的作用。

方法

5-8 组小鼠进行后爪切口。使用琥珀酰亚胺基水杨酰胺和漆树酸分别抑制组蛋白去乙酰化酶和组蛋白乙酰转移酶。使用热和机械敏化以及痛觉过敏引发的行为测量来评估。使用信使 RNA 定量和染色质免疫沉淀分析来研究 CXCR2 和配体表达的调节。最后，鞘内给予选择性 CXCR2 拮抗剂 SB225002，以揭示后爪切口后脊髓 CXCR2 受体的功能。

结果

琥珀酰亚胺基水杨酰胺显著加重切口后的机械敏化。相反，漆树酸减少了切口引起的敏化，并减弱了切口引起的痛觉过敏引发。总体而言，切口后脊髓组织中赖氨酸 9 上的组蛋白 H3 乙酰化增加，并且观察到赖氨酸 9 上的乙酰化组蛋白 H3 与 CXCR2 和角质形成细胞衍生趋化因子（CXCL1）的启动子区域的增强关联。阻断 CXCR2 逆转了后爪切口后的机械性痛觉过敏。