AhR调控IEL-IEC crosstalk在维护肠黏膜稳态中的作用及机制研究

Intestinal intraepithelial lymphocytes (IELs) play an important role in the interaction between intestinal epithelial cells (IECs) and gut immune cells. The crosstalk between IELs and IECs has been shown to be closely involved in the regulation of intestinal barrier homeostasis. Our previous studies have shown that both IEL-derived keratinocyte growth factor (KGF) and IEC-derived IL-7 play important roles in this crosstalk; however, the mechanism of this regulation has not been well understood. It has been shown that aryl hydrocarbon receptor (AhR) could regulate IEL-IEC crosstalk in the maintenance of intestinal barrier homeostasis. Several lines of evidence suggested that AhR could regulate IL-7 and KGF expression, as well as other cytokines from IELs or IECs. We hypothesize that AhR is a key transcription factor linking IEL-IEC crosstalk to the intestinal barrier homeostasis. In this study, we will investigate the role of AhR in the maintenance of intestinal barrier function. The changes of IEL subtypes and functions will also be studied. Furthermore, the effects of AhR activation on the expression of IL-7 and KGF in the crosstalk between IEL and IEC will be investigated. Moreover, we will investigate the role of cytokines derived from IEL in the regulation of intestinal barrier function. This proposal would give insight into the mechanism of AhR in maintaining intestinal barrier homeostasis and may provide novel strategy to prevent the loss of intestinal barrier function.

肠上皮间淋巴细胞（IEL）是肠道免疫系统参与肠上皮细胞（IEC）互动的重要细胞，IEL-IEC crosstalk机制在肠黏膜屏障（IEB）稳态维持中发挥重要作用。我们前期研究显示：IEL源KGF与IEC源IL-7在该机制中扮演重要角色，但其调控机制仍需进一步阐明。研究表明，芳香烃受体（AhR）是协调IEL-IEC crosstalk，维持肠黏膜稳态的关键连接点；另有证据提示：AhR还可能通过调控IL-7及KGF在IEL-IEC crosstalk中发挥重要作用，并参与多个IEL及IEC源细胞因子的调控。为此，本课题拟观察AhR在IEB稳态维持中的作用及对IEL表型和功能的影响，研究IL-7及KGF在AhR调控 IEL-IEC crosstalk中的作用，明确IEL源细胞因子在AhR调控IEB功能中的作用及机制。阐明AhR在维护IEB稳态中的关键作用，为IEB保护提供新策略。

肠上皮间淋巴细胞（IEL）是肠道免疫系统参与肠上皮细胞（IEC）互动的重要细胞，IEL-IEC crosstalk机制在肠黏膜屏障（IEB）稳态维持中发挥重要作用。我们前期研究显示：IEL源KGF与IEC源IL-7在该机制中扮演重要角色，但其调控机制仍需进一步阐明。.研究表明，芳香烃受体（AhR）是协调IEL-IEC crosstalk，维持肠黏膜稳态的关键连接点；另有证据提示：AhR还可能通过调控IL-7及KGF在IEL-IEC crosstalk中发挥重要作用，并参与多个IEL及IEC源细胞因子的调控。因此，我们推测AhR可能通过多种信号通路以及其它相关细胞因子的表达参与IEC-IEL crosstalk。.本项目利用AhR敲除小鼠、化学合成特异性siRNA干扰以及AhR激动剂，观察到AhR在多种肠道疾病中均起到了对肠黏膜的保护作用。同时，我们发现其作用机制是复杂多样的。在DSS诱导的小鼠结肠炎模型中，AhR通过调控TTP缓解了肠上皮炎性损伤，同时，AhR的活化上调了肠上皮间CD8αα+TCRαβ+IELs的数量和比例；在结直肠癌的发生中，AhR通过调控KGF促进了结直肠癌细胞LoVo和Caco-2的增殖，并且促进细胞周期从G0/G1期进入S期；在急性肠梗阻小鼠模型中，AhR活化后，通过抑制MLCK-pMLC磷酸化通路来促进了肠上皮细胞紧密连接蛋白的形成，从而保护了肠黏膜屏障。.通过本项目以上研究，我们阐明了AhR在维护IEB稳态中的关键作用，不仅能够完善肠黏膜屏障功能调控的分子机制，也将为临床结肠炎等疾病的治疗提供理论依据，为肠黏膜屏障保护提供新策略。