Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions
Inhibition of CCL1-CCR8 interaction prevents aggregation of macrophages and development of peritoneal adhesions
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DOI：
10.4049/jimmunol.178.8.5296
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Dohi, Taeko
中科院分区：
文献类型：
--
作者：
Hoshino, Akiyoshi;Kawamura, Yuki I.;Dohi, Taeko
腹膜粘连是手术和内脏炎症的重要并发症；然而，其机制尚未完全阐明。本研究的目的是通过关注腹膜腔内的细胞运输和免疫系统来阐明腹膜粘连的机制。我们研究了术后和炎症后腹膜粘连的小鼠模型中腹膜巨噬细胞（PM phi）的特异性募集及其趋化因子受体的表达。在这些小鼠腹膜粘连模型中，PM phi 聚集在腹膜损伤部位。与初始 PM phi 相比，聚集 PN phi 中趋化因子受体 CCR8 上调。在用细菌成分和细胞因子等炎症刺激剂处理的 PM phi 中也观察到了 CCR8 的上调，但在骨髓来源的 M phi 中没有观察到 CCR8 的上调。重要的是，CCL1 是 CCR8 的配体，是炎症刺激后 PM phi 和腹膜间皮细胞 (PMC) 的产物，是 CCR8 表达的有效增强剂。在 CCL1 存在的情况下，体外诱导了涉及 PM phi 和 PMC 的细胞聚集。 CCL1 还上调 PM phi 和 PMC 中纤溶酶原激活剂抑制剂-1 的 mRNA 水平。 CCR8 基因缺陷小鼠或用抗 CCL1 中和抗体治疗的小鼠表现出术后腹膜粘连显着降低。我们的研究现在建立了 PM phi 中独特的自分泌激活系统，以及通过 CCL1/CCR8 招募 PM phi 与 PMC 的机制，作为腹膜腔的免疫反应，从而引发腹膜粘连。
Peritoneal adhesions are a significant complication of surgery and visceral inflammation; however, the mechanism has not been fully elucidated. The aim of this study was to clarify the mechanism of peritoneal adhesions by focusing on the cell trafficking and immune system in the peritoneal cavity. We investigated the specific recruitment of peritoneal macrophages (PM phi) and their expression of chemokine receptors in murine models of postoperative and postinflammatory peritoneal adhesions. PM phi aggregated at the site of injured peritoneum in these murine models of peritoneal adhesions. The chemokine receptor CCR8 was up-regulated in the aggregating PN phi when compared with naive PM phi. The up-regulation of CCR8 was also observed in PM phi, but not in bone marrow-derived M phi, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PM phi and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. Cell aggregation involving PM phi and PMCs was induced in vitro in the presence of CCL1. CCL1 also up-regulated mRNA levels of plasminogen activator inhibitor-1 in both PM phi and PMCs. CCR8 gene-deficient mice or mice treated with anti-CCL1-neutralizing Ab exhibited significantly reduced postoperational peritoneal-adhesion. Our study now establishes a unique autocrine activation system in PM phi and the mechanism for recruitment of PM phi together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity, which triggers peritoneal adhesions.