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

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.

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。

肠道免疫微环境变化在克罗恩病的疾病进程中扮演了重要角色，如何从肠道免疫细胞的角度揭示肠道免疫微环境的调控策略是探索并开发克罗恩病新型治疗策略的重要手段。固有淋巴细胞（Innate Lymphoid Cell，ILC）作为肠道免疫微环境重要的组成部分，其在克罗恩病发生发展中的作用尚未完全阐明。我们的研究发现克罗恩病患者肠道组织内存在3型ILC（ILC3）与1型ILC（ILC1）间转化，并且这种转化通过影响CD4+ T细胞的炎性应答，促进克罗恩病小鼠模型的进程。如何逆转ILC3/ILC1转化来治疗克罗恩病？我们发现磷酸酶Wip1是调控ILC3/ILC1转化的重要胞内信号，依赖于p38信号通路。因此，我们的研究揭示磷酸酶Wip1调控ILC3/ILC1转化，促进CD4+ T细胞炎症应答，并进一步影响克罗恩病结局，靶向磷酸酶Wip1能够为开发克罗恩病新型治疗策略提供新思路。