Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice
Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice
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DOI：
10.1160/th10-08-0516
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发表时间：
2011-05-01
影响因子：
6.7
通讯作者：
Matsuo, Osamu
中科院分区：
文献类型：
--
作者：
Kawao, Naoyuki;Nagai, Nobuo;Matsuo, Osamu
尿激酶型纤溶酶原激活物(u-PA)通过激活肝脏中的纤溶酶原在组织重塑中发挥重要作用，但其作用机制尚不清楚。在这里，我们研究了u-PA参与肝脏修复过程中受损部位巨噬细胞的聚集和表型异质性。光化学反应诱导小鼠肝损伤后，对随后的病理反应和激活的巨噬细胞表型标志物的表达进行组织学分析。损伤部位的纤溶活性也通过纤维蛋白酶谱进行检测。在野生型小鼠中，损伤程度逐渐减少，直到第14天，并与损伤部位边缘巨噬细胞的聚集有关。此外，在第7天，聚集在损伤组织附近的巨噬细胞表达CD206，这是高吞噬功能的巨噬细胞的标志。此外，与CD206阳性细胞相邻的巨噬细胞表达促炎标记诱导型一氧化氮合酶(INOS)，在第4天和第7天，u-PA活性在损伤部位增强，主要分布在交界区。相反，在u-PA缺乏的小鼠中，损伤大小的减小和巨噬细胞的聚集都受到了损害。此外，在u-PA缺乏的小鼠，CD206和iNOS在聚集在边缘区域的巨噬细胞中都没有表达。缺乏u-PA受体(u-PAR)或组织型纤溶酶原激活剂基因的小鼠在肝脏修复期间可以正常恢复。这些数据表明，u-PA通过u-PAR不依赖的机制介导巨噬细胞的聚集及其在受损部位边缘的表型异质性。
Urokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated macrophages were analysed histologically. Fibrinolytic activity at the damaged site was also examined by fibrin zymography. In wild-type mice, the extent of damage decreased gradually until day 14 and was associated with an accumulation of macrophages at the border of the damaged site. In addition, the macrophages that accumulated near the damaged tissue expressed CD206, a marker of highly phagocytic macrophages, on day 7. Further, macrophages that were adjacent to CD206-positive cells expressed inducible nitric oxide synthase (iNOS), a pro-inflammatory marker, u-PA activity increased at the damaged site on days 4 and 7, which distributed primarily at the border region. In contrast, in u-PA-deficient mice, the decrease in damage size and the accumulation of macrophages were impaired. Further, neither CD206 nor iNOS was expressed in the macrophages that accumulated at the border region in u-PA-deficient mice. Mice deficient for the gene encoding either u-PA receptor (u-PAR) or tissue-type plasminogen activator experienced normal recovery during liver repair. These data indicate that u-PA mediates the accumulation of macrophages and their phenotypic heterogeneity at the border of damaged sites through u-PAR-independent mechanisms.