Role of intraperitoneal cell-traffic and TGF superfamily members in inflammatory bowel diseases

本研究的目的是通过聚焦腹腔内的细胞运输和免疫系统，阐明炎症性肠病小鼠模型中炎症细胞浸润的机制。最初，我们发现结肠炎诱导后腹膜渗出液中巨噬细胞大量减少，未成熟粒细胞型细胞数量增加。我们研究了通过荧光标记的腹腔巨噬细胞过继转移对腹腔巨噬细胞的特异性募集（PMФs），以及它们趋化因子受体的表达。PMФs聚集在结肠受伤的浆膜侧。与幼稚的PMФs相比，趋化因子受体CCR8在聚集的PMФs中上调。在PMФs中也观察到CCR8的上调，但在用包括细菌成分和细胞因子在内的炎症刺激物治疗的骨髓源性巨噬细胞中没有观察到。重要的是，CCR8的配体CCL1是炎症刺激后PMФs和腹膜间皮细胞（PMCs）的产物，是CCR8表达的有效增强剂。lps挑战PMФs也产生tgf超家族成员激活。CCL1在体外诱导PMФand PMCs细胞聚集。CCR8基因缺陷小鼠或抗ccl1中和抗体处理小鼠血清巨噬细胞积累显著减少。我们的研究现在在PMФ中建立了一个独特的自分泌激活系统，以及通过CCL1/CCR8募集PMФs和PMCs作为腹腔免疫应答的机制。在这里，我们发现了一种有效的防御机制，作为腹膜巨噬细胞的特定功能，当炎症或手术应激到达身体深处时。

The aim of this study was to clarify the mechanism of inflammatory cell infiltration in mouse model of inflammatory bowel disease by focusing the cell trafficking and immune system in the peritoneal cavity. Initially we found great loss of peritoneal macrophages in peritoneal exudate after induction of colitis and increased number of immature granulocyte-type cells. We investigated the specific recruitment of peritoneal macrophages (PMФs) by adoptive transfer of fluorescence-labeled peritoneal macrophages, and their expression of chemokine receptors. PMФs aggregated at the site of injured serosal side of the colon. The chemokine receptor CCR8 was upregulated in the aggregating PMФs when compared with naive PMФs. The upregulation of CCR8 was also observed in PMФs, but not in bone marrow-derived macrophages, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMФs and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. LPS-challenged PMФs also produced a TGF-superfamily member activin. Cell aggregation involving PMФand PMCs was induced in vitro in the presence of CCL1. CCR8 gene deficient mice or mice treated with anti-CCL1 neutralizing antibody exhibited significantly reduced serosal macrophage accumulation. Our study now establishes a unique autocrine activation system in PMФ and the mechanism for recruitment of PMФs together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity. Here we found an efficient defense mechanism as a specific function of peritoneal macrophages when inflammatory or surgical stress reaches to the deep inside of the body.