IL-33/ST2信号轴介导SPINK/Spink1基因突变相关慢性胰腺炎纤维化的机制研究

慢性胰腺炎（CP）以胰腺实质广泛损害及纤维化为特征，发病机制尚不明确，缺乏有效早期干预手段。我们根据前期研究锚定的中国人群特征性CP易感基因SPINK1 c.194+2T＞C突变，首次成功构建了Spink1突变小鼠模型，该小鼠自发出现胰腺纤维化等CP典型病理表现。为明确CP的发病机制，精准定位治疗靶点，我们对突变小鼠进行了表达谱芯片分析、单细胞测序及验证等预实验发现：腺泡细胞分泌的IL-33水平显著上调，其靶细胞巨噬细胞发生M2极化，星状细胞激活水平增高。因此，我们推测IL-33通过受体ST2诱导巨噬细胞M2极化及星状细胞激活，并进一步引起二者正反馈相互作用，最终导致胰腺纤维化。本研究拟通过细胞实验明确IL-33/ST2信号轴引起M2巨噬细胞及星状细胞相互作用，通过在体实验检验IL-33/ST2信号轴阻断对胰腺纤维化的治疗价值，最终明确SPINK1突变的致病机制，为CP的早期干预提供靶点。

Chronic pancreatitis (CP) is a nonreversible disease featured by prolonged inflammatory damage of pancreas parenchyma and global fibrosis. In previous studies, we focused on the characteristic genetic mutation SPINK1 c.194+2T＞C mutation and successfully constructed the first Spink1 mutant transgenetic mouse model in the world. Spink1 mutant mice spontaneously presented with typical CP pathological changes including pancreatic fibrosis. In order to address the pathogenesis of CP and find therapeutic targets, we next performed gene chip assay, single cell sequencing analysis and subsequent validation experiments on Spink1 mutant mice to find that IL-33 secreted by injured acinar cell is significantly upregulated in Spink1 mutant mice. Moreover, macrophages and pancreatic stellate cells, the target cells of IL-33, have respectively went through M2 polarization and enhanced activation. Thus, we infer that IL-33 may act through its receptor ST2 to induce macrophage M2 polarization and pancreatic stellate cells activation to further mediate their positive feedback interaction. Finally, IL-33 signaling results in pancreatic fibrosis. In the present study, the mechanism of interaction between M2 polarized macrophages and pancreatic stellate cells mediated by IL-33/ST2 signal axis will be elucidated through in-vitro experiments. Also, the therapeutic value of IL-33/ST2 signal axis blocking for pancreatic fibrosis will be tested in-vivo. The aim of this present study is to clarify the pathogenic mechanism of SPINK1 mutation and to provide targets for early intervention of CP.