miR-31调控巨噬细胞代谢重编程在银屑病中的作用机制

Psoriasis is a common chronic inflammatory skin disease, macrophages provide specific signals involved in the initiation and maintenance of its pathogenesis. A growing number of evidences highlight a crucial role of metabolic reprogramming in the activation of macrophages. The metabolic adaptations to changes in psoriasis, such as inflammatory as well as anti-inflammatory macrophages are thought to be critical for the development of psoriasis, the underlying mechanism remains unclear. In our recent studies, we have observed that an intrinsic microRNA, miR-31 was markedly increased in F4/80+MHCII+ macrophages subset derived from lesional skin of IMQ-induced mouse model of psoriasis. We further found that increased miR-31caused dysfunction of glycolysis and OXPHOS in macrophages. We have established miR-31 and its target gene PP6 conditional knockout mouse models in which miR-31 and PP6 are selectively deleted in macrophages (lysMCre- miR-31fl/fl and lysMCre-PP6fl/fl). Following our original studies, this project intends to deeply investigate three research directions, 1. Mechanisms underlying the immunometabolism of macrophages regulated by miR-31 and PP6. 2. The biological functions of various macrophage subsets which were controlled by metabolic reprogramming in psoriasis. 3. Exploring the key molecule(s) that regulates macrophage metabolism to possibly pave a way for developing novel targeted drugs with less side-effects and long-term efficacy.

巨噬细胞在银屑病发病进程中提供了启动和维持发病的特殊信号。然而，巨噬细胞在银屑病炎症微环境中促炎与抗炎的动态变化机制仍不得而知。近期研究表明，免疫代谢的调控可能成为揭示巨噬细胞参与银屑病发病的重要分子机理。申请人前期研究发现：咪喹莫特诱导的小鼠类银屑病模型中，miR-31在真皮组织F4/80+MHCII+的巨噬细胞亚群中明显高表达，且通过靶向抑制细胞内重要的磷酸化酶PP6进一步促使巨噬细胞糖酵解能力与氧化磷酸化代谢途径的异常，从而操控巨噬细胞向促炎方向的极化。课题组已构建miR-31及PP6在巨噬细胞中条件性敲除小鼠，拟深入研究：1. miR-31靶向PP6调控巨噬细胞免疫代谢的分子机制；2.代谢重编程操控不同巨噬细胞亚群在银屑病发病进程中的生物学功能；3.寻找干预巨噬细胞代谢的关键节点，为开发靶向性强、副作用小、长期疗效好的银屑病治疗方法提供新思路。

树突细胞和巨噬细胞是皮肤感知“危险信号”的最初效应细胞，巨噬细胞作为天然免疫的重要元件，在调控组织稳态中起到了重要的作用。此项课题发现了银屑病炎性皮肤组织中一群具有高抗原提呈功能、高炎性的巨噬细胞亚群，我们解析了此亚群的细胞特性及关键的调控分子—PP6（Serine/threonine protein phosphatase 6），作为miR-31重要的靶标，我们鉴定出PP6下游调控蛋白—PFKFB3，PFKFB3作为糖酵解的关键激活酶，以代谢重编程机制角度阐述了一群炎性巨噬细胞在银屑病发生、发展中的重要作用。申请人在完成此项课题的同时，利用前沿的技术在慢性炎症性疾病发病与复发机制的研究中取得了一些相关的研究成果，均得到本项目资助，并作为共同第一作者发表文章：1、揭示了银屑病患者皮肤中DC2细胞识别并提呈“自身核酸抗原复合物”，是引发银屑病反复发作的重要因素（Immunity，2020）；2、发现长链非编码RNA-MIR155HG编码的内源性多肽通过调控树突状细胞功能从而调节慢性炎症性疾病的发展（Science Advances，2020）；3、在本项目的支持下申请了国家发明专利一项。申请人通过本项目及相关研究对天然免疫细胞在银屑病发病中的作用机制有了更深入的理解，有望为炎症性疾病提供精准靶向治疗策略。