Phosphatase Wip1 Masters IL-17-producing Neutrophil-mediated Colitis in Mice
Phosphatase Wip1 Masters IL-17-producing Neutrophil-mediated Colitis in Mice
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DOI：
10.1097/mib.0000000000000751
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发表时间：
2016-06-01
影响因子：
4.9
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
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作者：
Hu, Xuelian;Wang, Peng;Zhao, Yong
野生型P53诱导的磷酸酶1(Wip1)目前被认为是一种很有前途的癌症治疗药物靶点。我们最近的研究表明，Wip1的缺失显著促进了中性粒细胞的炎症反应。Wip1是否参与炎症性肠病的调控尚不清楚。在本研究中，我们发现Wip1基因敲除(KO)小鼠比野生型小鼠更容易感染葡聚糖硫酸钠(DSS)诱导的结肠炎，Wip1基因敲除小鼠的存活率较低，体重迅速减轻，疾病活动指数增加，结肠长度较短，结肠病理较重。利用全骨髓嵌合体小鼠模型，我们证明了Wip1本质上控制免疫细胞的炎症反应。IL-17(Wip1/IL-17双KO小鼠)的缺失显著挽救了Wip1KO小鼠的病理改变。DSS处理的野生型和Wip1KO小鼠的中性粒细胞表达显著更高的IL-17。在将分选的Wip1KO或双KO中性粒细胞过继转移到IL-17KO小鼠体内后，接受双KO中性粒细胞移植的小鼠比接受Wip1KO中性粒细胞移植的小鼠对DSS诱导的结肠炎更具抵抗力。这些数据共同表明，Wip1通过内在地调节免疫细胞来调节宿主对结肠炎的敏感性。Wip1KO小鼠中性粒细胞IL-17表达增强导致结肠炎的敏感性和严重性增加。因此，Wip1可能成为治疗结肠炎的药物靶点。
Wild-type p53-induced phosphatase 1 (Wip1) is currently believed to be a promising drug target for cancer therapy. Our recent studies showed that deletion of Wip1 remarkably promoted neutrophil inflammatory response. Whether Wip1 is involved in the regulation of inflammatory bowel disease is unknown. In the present study, we found that Wip1 knockout (KO) mice were more susceptible to colitis induced by dextran sulphate sodium (DSS) than wild-type mice as substantiated by the lower mouse survival ratio, rapid bodyweight loss, increased disease activity index, shorter colon length, and more severe pathology of colons in Wip1KO mice. Using full bone marrow chimera mouse models, we demonstrated that Wip1 intrinsically controls inflammatory response of immune cells. Deletion of IL-17 (Wip1/IL-17 double KO mice) significantly rescued the pathology in Wip1KO mice. Neutrophils of DSS-treated wild-type and Wip1KO mice expressed significantly higher IL-17. After adoptive transfer of sorted Wip1KO or double KO neutrophils into IL-17KO mice, mice receiving double KO neutrophils were more resistant to DSS-induced colitis than mice receiving Wip1KO neutrophils. These data collectively indicate that Wip1 modulates host sensitivity to colitis by intrinsically regulating immune cells. The enhanced IL-17 expression in neutrophils contributed to the increased sensitivity and severity of colitis in Wip1KO mice. Thus, Wip1 may be used as a drug target to treat colitis.