Wnt5a/β-catenin信号通路与炎症信号的交叉互动在寻常型银屑病免疫应答中的分子机制

Psoriasis is a common chronic inflammatory disease, which is characterized by the infiltration of multiple immune cells, keratinocyte proliferation and poorly differentiated, and increased dermal vascularity. Wnt signaling has been reported to be involved in their proliferation, migration and survival. Our previous studies showed that Wnt pathway was abnormal expressed in psoriasis lesions and Wnt5a plays a dual role in the β-catenin pathway. But the underlying mechanisms of the interaction of Wnt5a/β-catenin signaling pathway, immune cells and inflammatory cytokines, remained unclear. We hypothesized that activation of Wnt5a is involved in the proliferation of Keratinocytes and the secretion of inflammatory cytokines, which further regulate the expression of Wnt5a and promote the proliferation and activation of Keratinocytes through the Wnt5a/β-catenin signaling pathway. The cross-talk forms a signal loop to promote the persistence of psoriasis inflammation and disease progression. This project aims to investigate the cross-talk of Wnt5a/β-catenin signaling pathway and the activity of T lymphocytes, dendritic cells and neutrophil, and inflammatory factors. And their effect on the progression of psoriasis by using Imatinot-induced psoriasis model, KRT14-cre × Wnt5afl/fl transgenic mice and cell model. We would like to clarify the impact of disease progression and their molecular mechanisms by interposing the cross-talk loop of Wnt5a/β-catenin and inflammatory signaling pathways. And then, to provide theoretical and experimental basis for the treatment of psoriasis with Wnt5a as the target and the intervention of immune response loop.

寻常型银屑病皮损中Wnt信号通路异常活化，我们前期研究发现 Wnt5a对β-catenin通路具有双重调节作用。但银屑病发病过程中Wnt5a/β-catenin信号通路与免疫细胞应答、炎性因子的关系尚不清楚。我们假设Wnt5a的活化参与KC增殖及免疫细胞分泌炎症因子，反过来调控Wnt5a的表达，通过上述通路促进KC增殖和活化。两者交叉互动形成环路，促使银屑病炎症持续存在，疾病进展。本项目拟针对以上假说，通过建立咪喹莫特诱发银屑病模型、KRT14-cre× Wnt5afl/fl转基因小鼠及细胞模型，应用Wnt5a、β-catenin激活剂，分析Wnt5a/β-catenin信号通路与T淋巴细胞、DCs、中性粒细胞活性及炎症因子的交互影响在银屑病发生发展中的作用，明确干预该通路与炎症信号的交叉环路对疾病进展的影响及分子机制，为针对Wnt5a为靶点及干预免疫应答环路治疗银屑病提供理论和实验依据。

项目背景：银屑病是一种表皮増殖过速、角化不全的常见慢性炎症性疾病，表现为角质形成细胞（keratinocytes，KC）的过度增生与异常分化、细胞间粘附力不足、屏障功能降低，真皮浅层毛细血管增生、扩张以及炎症细胞的浸润。由于其反复发作、病因不明、临床表现多样、严重影响患者生活质量，该病一直是学术界研究的重点。虽然目前很多药物缓解寻常型银屑病，但缺乏有效预防的方法。因此，明确银屑病发病机制，寻找关键干预靶点进而阻止或逆转其病理进程对于银屑病的有效防治具有重要意义。.主要研究内容：1.IMQ诱导银屑病小鼠皮损上皮间质转化 2.银屑病皮损中Wnt5a改变及Wnt5a KO小鼠中银屑病样皮炎表型改变 3.长期的咪喹莫特刺激对小鼠骨质的影响 4.Wnt5a KO和同窝小鼠银屑病皮损转录组分析.结果：IMQ诱导银屑病样皮损上皮间质转化，长期的咪喹莫特涂抹诱导骨丢失及骨微观结构改变。然而，小鼠皮损转录组数据分析显示Wnt5a KO小鼠相较于同窝野生小鼠皮损差异基因表达显著。因此，Wnt5a在IMQ诱导的银屑病样皮炎中仍扮有重要作用，但是或许不影响银屑病相关免疫细胞的特性。.结论：通过以上研究，对银屑病发病机制有了进一步认识，初步建立了银屑病合并骨丢失等复合模型，为相关研究乃至银屑病防治药物的研究提供了模型基础和理论依据。