磷酸酶Wip1介导固有淋巴细胞转化调控克罗恩病的机制研究

克罗恩病（CD）的发生、发展与肠道免疫应答失调密切相关，探讨肠道免疫细胞的调控机制是改变治疗预后的关键。最新发现，固有淋巴细胞（ILC）对肠道微环境稳定具有重要调控作用，CD患者肠内存在ILC3/ILC1转化，然而其临床意义及相关机制尚未阐明。我们前期研究发现磷酸酶Wip1在活动期CD患者回肠ILC内表达量显著下调，在体外，Wip1抑制剂可以促进ILC3/ILC1转化，提示Wip1可能内源性调控ILC；运用ILC特异性缺失Wip1的小鼠构建肠炎模型，小鼠体重显著下降，且肠内ILC3/ILC1转化比例显著增高，与此同时，表达IL-17A及IFN-γ的CD4+T细胞比例显著增高，提示Wip1可能通过内源性调控ILC3/ICL1转化，影响CD4+T细胞的炎症应答。据此我们拟运用多系基因敲除小鼠及临床样本，深入探索Wip1调控ILC3/ILC1转化的细胞及分子机制，为CD治疗提供新的思路。

Crohn's disease (CD) is an aberrant immune response that occurs in genetically susceptible individuals. Understanding the changes of immune cells and its regulatory mechanism is the key to reversing the dysregulated immune response and changing the disease outcome. Type 3 innate lymphocyte (ILC3) is the newly discovered group that plays an important regulatory role in the stability of gut microenvironment. However, ILC3 is converted to ILC1 in the intestinal tract of CD patients. The significance of this ILC3/ILC1 conversion in CD and the molecular mechanism in regulating this conversion has not yet been clarified. Our previous work revealed the regulation of neutrophils by phosphatase Wip1 in murine colitis; further studies showed that Wip1 was significantly down-regulated in ILC in patients with active CD, and Wip1 inhibitor in vitro significantly increased the percentage of ILC3 to ILC1,suggesting that Wip1 may intrinsically regulate the changes of ILC in CD. To further explore the role of Wip1 in regulating ILC, we developedcolitis using mice with specific deletion of Wip1 in ILC, and found that the body weight of mice was significantly reduced and the ratio of ILC3 to ILC1 in the intestine was significantly higher. In addition,the proportion of CD4+ T cells expressing IL-17A and IFN-γ was also significantly increased, suggesting that Wip1 can affect the inflammatory response of CD4+ T cells by endogenous regulation of ILC3 / ICL1. Therefore, we intend to use a variety of gene knockout mice and clinical samples to further explore the biological significance and molecular mechanism of Wip1 regulation ILC3 / ILC1 conversion for future benefits of CD.