Treatment with Recombinant Trichinella spiralis Cathepsin B-like Protein Ameliorates Intestinal Ischemia/Reperfusion Injury in Mice by Promoting a Switch from M1 to M2 Macrophages
Treatment with Recombinant Trichinella spiralis Cathepsin B-like Protein Ameliorates Intestinal Ischemia/Reperfusion Injury in Mice by Promoting a Switch from M1 to M2 Macrophages
复制标题
使用重组旋毛虫组织蛋白酶 B 样蛋白治疗可促进 M1 巨噬细胞向 M2 巨噬细胞的转换，从而改善小鼠肠道缺血/再灌注损伤。
DOI：
10.4049/jimmunol.1401864
复制
发表时间：
2015-07-01
影响因子：
4.4
通讯作者：
Liu, Ke-Xuan
中科院分区：
文献类型：
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作者：
Liu, Wei-Feng;Wen, Shi-Hong;Liu, Ke-Xuan
肠缺血/再灌注（I/R）损伤可导致高发病率和死亡率，其中巨噬细胞起着关键作用。从经典激活的（M1）巨噬细胞向替代激活的（M2）巨噬细胞的转变依赖于STAT6信号通路的激活，已被证明可保护器官免受I/R损伤。在本研究中，我们研究了重组旋毛虫组织蛋白酶B样蛋白（rTsCPB）对肠I/R损伤的影响以及与巨噬细胞表型转换相关的潜在机制。在一个经历60分钟肠缺血随后进行2小时或7天再灌注的小鼠I/R模型中，我们证明肠I/R导致了显著的肠损伤，并诱导了从M2到M1巨噬细胞的转变，这表现为M2标志物（精氨酸酶 - 1和炎症区发现蛋白）水平降低，M1标志物（诱导型一氧化氮合酶和CCR7）水平升高，以及M2/M1巨噬细胞比例降低。rTsCPB逆转了肠I/R诱导的M2 - M1转变，并促进了M1 - M2表型转换，表现为M1标志物显著降低，M2标志物增加，以及M2/M1巨噬细胞比例升高。同时，rTsCPB显著改善了肠损伤，提高了动物的肠道功能和存活率，伴随着肠道中性粒细胞浸润减少和细胞增殖增加。然而，一种选择性STAT6抑制剂AS1517499通过抑制M1到M2的转变逆转了rTsCPB的保护作用。这些发现表明肠I/R损伤导致从M2到M1巨噬细胞的转变，并且rTsCPB通过促进依赖STAT6的M1到M2转变来改善肠损伤。
Intestinal ischemia/reperfusion (I/R) injury, in which macrophages play a key role, can cause high morbidity and mortality. The switch from classically (M1) to alternatively (M2) activated macrophages, which is dependent on the activation of STAT6 signaling, has been shown to protect organs from I/R injuries. In the current study, the effects of recombinant Trichinella spiralis cathepsin B-like protein (rTsCPB) on intestinal I/R injury and the potential mechanism related to macrophage phenotypes switch were investigated. In a mouse I/R model undergoing 60-min intestinal ischemia followed by 2-h or 7-d reperfusion, we demonstrated that intestinal I/R caused significant intestinal injury and induced a switch from M2 to M1 macrophages, evidenced by a decrease in levels of M2 markers (arginase-1 and found in inflammatory zone protein), an increase in levels of M1 markers (inducible NO synthase and CCR7), and a decrease in the ratio of M2/M1 macrophages. RTsCPB reversed intestinal I/R-induced M2-M1 transition and promoted M1-M2 phenotype switch evidenced by a significant decrease in M1 markers, an increase in M2 markers, and the ratio of M2/M1 macrophages. Meanwhile, rTsCPB significantly ameliorated intestinal injury and improved intestinal function and survival rate of animals, accompanied by a decrease in neutrophil infiltration and an increase in cell proliferation in the intestine. However, a selective STAT6 inhibitor, AS1517499, reversed the protective effects of rTsCPB by inhibiting M1 to M2 transition. These findings suggest that intestinal I/R injury causes a switch from M2 to M1 macrophages and that rTsCPB ameliorates intestinal injury by promoting STAT6-dependent M1 to M2 transition.