腺苷/AMPK信号通路促红细胞氧气释放拮抗寻常型银屑病皮肤组织损伤的作用及机制研究

Psoriasis vulgaris, a recurrent chronic disease with high incidence and refractory course, largely affects the victims’ life quality, and its current therapeutic strategies are limited along with drug-resistance and adverse reactions. Therefore, to explore effective approaches to counteract psoriasis vulgaris is important. Hypoxia and chronic inflammation contributes to the development and progression of the pathological process of psoriasis vulgaris. By utilizing blood samples of psoriasis vulgaris patients and IMQ-induced psoriasis mouse model, coupled with metabolomics and mouse genetics, we showed that adenosine signaling induces erythrocyte 2,3-BPG level under psoriasis vulgaris condition, facilitating the release of oxygen, and thereby counteracts local tissue injury. Further studies revealed that psoriasis-induced elevation of erythrocyte AMPK activity and tissue ROS level and HIF-1α activity were positively correlated to plasma adenosine level both in psoriasis vulgaris patients and mouse models. Based on our previous works, we proposed a novel hypothesis that under psoriasis vulgaris condition, adenosine ADROA2B signaling coupled with AMPK induces 2,3-BPG, and subsequently promotes oxygen release and tissue oxygen supply, therefore decreases ROS level and inhibits HIF-1α to prevent tissue injury. This project is to explore the underlying mechanism of AMPK regarding the regulation of 2, 3-BPG, to reveal the potential mechanism of the beneficial role of adenosine signaling-mediated oxygen release in psoriasis-induced tissue protection. Taken together, this study will identify new mechanism regarding the beneficial role of erythroid in response to psoriasis vulgaris, and provide novel strategy for treatment of psoriasis.

寻常型银屑病发病率逐年递增、病程迁延难愈，严重影响患者身心健康。其治疗手段有限且常出现耐药及不良反应，挖掘其发病机制并研发新治疗途径迫在眉睫。研究已证实缺氧与慢性炎症参与银屑病的发生发展，申请人前期开展的患者临床样本研究提示：腺苷通路介导的红细胞氧气释放能力的增强，与银屑病皮损的严重程度呈负相关。动物模型预实验结果提示：腺苷通路能活化红细胞内AMPK、促进氧气释放、抑制皮损中ROS与HIF-1α水平。本项目科学假说：腺苷通路通过作用于红细胞内AMPK，磷酸化激活2,3-BPG生成限速酶以上调2,3-BPG合成，促进氧气释放，抑制皮损缺氧与ROS和HIF-1α的水平，减轻银屑病的局部组织损伤。本项目将阐述红细胞内AMPK下游促氧气释放的机制，探明腺苷通路调控局部组织氧供以减轻寻常型银屑病组织损伤的机制，并明确靶向调节腺苷通路对抗寻常型银屑病损伤的应用潜力。本项目将为银屑病的诊治提供新的思路。

寻常型银屑病发病率逐年递增、病程迁延难愈，严重影响患者身心健康。其治疗手段有限且常出现耐药及不良反应，挖掘其发病机制并研发新治疗途径迫在眉睫。在国家自然科学基金面上基金的资助下，我们在腺苷-腺苷受体轴在银屑病中的作用以及临床应用潜力方面取得了突破性进展，并拓展了腺苷-ADORA1轴在黑素瘤的其它相关研究，阐明了其在PD-L1转录调控及PD-1单抗联合治疗黑素瘤中的作用重要作用。在本基金的资助下，发表 SCI 研究论文 4 篇，其中有3 篇文章 IF>10.0，最高IF=26.602 (Cancer Cell)，具体内容详见成果部分。同时还有一篇文章在投。