Indomethacin inhibits eosinophil migration to prostaglandin D2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis
Indomethacin inhibits eosinophil migration to prostaglandin D2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis
复制标题
吲哚美辛抑制嗜酸性粒细胞向前列腺素 D2 迁移：CRTH2 脱敏治疗嗜酸性脓疱性毛囊炎的治疗潜力
DOI：
10.1111/imm.12112
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发表时间：
2013
期刊：
影响因子：
6.4
通讯作者：
Yokozeki H.
中科院分区：
文献类型：
--
作者：
Kataoka N;Satoh T;Hirai A;Saeki K;Yokozeki H.
吲哚美辛是一种环加氧酶抑制剂，对各种嗜酸性皮肤病，特别是嗜酸性脓疱性毛囊炎显示出治疗潜力。吲哚美辛的独特特征之一是，与其他非甾体抗炎药不同，它是一种在辅助性T细胞2型（CRTH 2）上表达的化学引诱物受体同源分子的强效激动剂，该分子是前列腺素D2（PGD 2）的受体。本研究探讨吲哚美辛对嗜酸性粒细胞迁移的药理作用，以阐明吲哚美辛治疗嗜酸性脓疱性毛囊炎的实际机制。嗜酸性粒细胞通过CRTH 2受体对PGD 2和吲哚美辛表现出趋化和趋化反应。用吲哚美辛预处理嗜酸性粒细胞极大地抑制了嗜酸性粒细胞向PGD 2的迁移，并在较小程度上抑制了嗜酸性粒细胞趋化因子（CCL 11）的迁移;这些作用可能分别通过吲哚美辛对CRTH 2的激动作用使嗜酸性粒细胞CRTH 2和CCR 3的同源和异源脱敏来介导。吲哚美辛还消除了PGD 2的血浆代谢产物Δ12-PGJ 2对嗜酸性粒细胞趋化因子的启动作用。吲哚美辛下调CRTH 2和CCR 3的细胞表面表达。嗜酸性脓疱周围的毛囊上皮和表皮角质形成细胞以及嗜酸性脓疱性毛囊炎掌跖病变的外分泌器官对脂质运载蛋白型PGD合酶呈化学染色阳性。吲哚美辛可能通过减少嗜酸性粒细胞对PGD 2的反应，对PGD 2-CRTH 2信号发挥主要作用的嗜酸性粒细胞皮肤病发挥治疗作用。
Indomethacin is a cyclo‐oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non‐steroidal anti‐inflammatory drugs, it is a potent agonist of chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2(PGD2). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2and indomethacin through CRTH2 receptors. Pre‐treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ12‐PGJ2, a plasma metabolite of PGD2, on eosinophil chemotaxis to eotaxin. Indomethacin down‐modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin‐type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2‐CRTH2 signals play major roles by reducing eosinophil responses to PGD2.