角蛋白17介导皮肤微血管异常参与银屑病发病的作用及机制研究

Highly dilated and tortuous capillaries with increased permeability in the papillary dermis are prominent pathological characteristics of psoriasis, but of which the regulatory mechanism remains unknown. Keratin 17 (K17), a keratin highly expressed in keratinocytes specifically when psoriasis occurs, constitutes a “K17 loop” in psoriatic pathogenesis by activating keratinocytes and synergistically recruiting various inflammatory cells. We have recently discovered such noticeable dilation and elevated permeability of the micro-vessels in the skin lesion of imiquimod-induced psoriasis-like mice, while both such vascular abnormality and psoriatic phenotype were greatly alleviated in K17 knocked-out mice. What’s more important, such a positive correlation between K17 expression and severity of microvascular dilation was also seen in the lesion of psoriatic patients. Therefore, we put forward that K17 expression participates in the psoriatic pathogenesis by regulating keratinocytes’ production of various mediators and promoting the chemotaxis of several immunocytes, which contributed to the increase of capillary permeability. In the present proposal, we plan to analyze the regulatory role of K17 in the skin micro-vascular permeability using the techniques of cytology, molecular biology and animal models. We also plan to identify the key cellular and molecular events that are responsible for the elevation of skin microvasluar permeability in psoriasis. Moreover, the significance of high microvasluar permeability in the pathogenesis of K17-mediated psoriasis shall be clarified, so that they will serve as key evidence to the study of psoriatic pathogenesis and potential targets for the treatment of psoriasis.

真皮乳头层血管的高度迂曲扩张及通透性增高是银屑病的突出病理改变，但其机制尚不清楚。角蛋白17（K17）是银屑病角质形成细胞特异性高表达的一种角蛋白，通过活化角质形成细胞、协同趋化多种炎细胞等作用构成银屑病发病的“K17环路”机制。我们近期发现，咪喹莫特诱导的小鼠银屑病样模型皮损处微血管明显扩张并伴通透性增高，而K17敲除小鼠的银屑病表型和皮肤微血管改变均明显减轻。对银屑病患者的研究也发现皮损K17的表达与微血管扩张程度呈正相关。因此认为，K17通过活化角质形成细胞、趋化炎细胞并释放多种介质等作用，造成微血管通透性增高等异常参与银屑病发病。本课题在前期工作的基础上，利用细胞、分生、动物模型等手段分析K17对皮肤微血管通透性的调节作用，揭示调控银屑病皮肤微血管异常的关键细胞和分子事件，明确微血管通透性增高等改变在K17介导的银屑病发病机制中的意义，为研究银屑病发病机制、指导治疗提供重要依据。

银屑病是常见的慢性炎症性皮肤病，临床表现为反复发作的有鳞屑覆盖的红斑、丘疹和斑块。研究表明，银屑病皮损真皮乳头层血管的扩张先于典型皮损的出现，提示其可能在银屑病发病的启动环节及加重过程中发挥关键作用，但其作用机制不清。本项目利用电镜及单细胞测序发现皮肤VEC在银屑病中的分子及超微结构改变，提出其并非通过血管再生，而是通过调控细胞黏附、调节局部微环境参与银屑病发病。利用K17特异性基因敲除小鼠证明角蛋白17通过调控中性粒细胞等多种免疫细胞黏附浸润参与银屑病发病，其中中性粒细胞是皮肤VEC功能的重要调节者。进一步机制研究发现，角蛋白17主要通过通过PI3k/AKT/NF-κB信号途径促进CXCL1等趋化因子的分泌，趋化中性粒细胞至皮损局部并分泌以MMP9为代表的蛋白水解酶，破坏血管屏障并增加其通透性，介导大量的免疫细胞向皮肤局部募集，最终导致银屑病的发病。本研究为进一步深入阐释银屑病发病机制提供了新思路，提出作为局部固有免疫成员之一的皮肤血管内皮细胞在银屑病的发病中发挥重要作用。