信号调节蛋白SIRPα调控巨噬细胞有氧糖酵解及炎症反应的机制

As important immune cells, macrophages and monocytes are central components of human innate immunity and many pathophysiological processes. Although leukocyte-specific signal regulatory protein α (SIRPα) plays a critical role in regulating each aspect of leukocyte inflammatory responses and innate immunity, the underlying mechanism, however, remains incompletely understood. The goal of this project is to identify the mechanism by which SIRPα regulates macrophage/monocyte inflammatory responses. In preliminary study, employing various monoclonal antibodies against different regions of SIRPα and SIRPα ITIM (immunoreceptor tyrosine inhibition motif)-deletion mice, we showed the negative regulation of SIRPα in leukocyte inflammatory responses. Meanwhile, we successfully generated the first SIRPα-knockout (SIRPα-KO) mice, providing a necessary tool for defining the role of SIRPα. We have also reported for the first time that SIRPα protein expression in macrophages is modulated by miR-17, miR-20a and miR-106a at posttranscriptional level. Importantly, our recent results showed that macrophage SIRPα could recruit SHP-1 and then directly dephosphorylated pyruvate kinase isozymes M2 (PKM2), and the decrease of PKM2 phosphorylation resulted in a lower aerobic glycolysis (Warburg effect) in macrophages and thus suppressed macrophage inflammatory responses. This project will base on these compelling preliminary results, continuously study the role of SIRPα in regulating macrophage inflammatory responses and its molecular basis. We believe that these studies will shed light to the understanding of innate immunity and inflammation regulation, and provide novel therapeutic targets for clinical prevention and treatment of various inflammation-related diseases.

巨噬细胞及其前体单核细胞在天然免疫及各种炎症相关疾病中扮演重要角色。大量研究表明白细胞特有的信号调节蛋白(SIRPα)对巨噬细胞炎症反应有重要调节作用，但其分子机制还不清楚。本课题的目标就是阐明SIRPα调控巨噬细胞炎症反应和天然免疫的作用机制。在前期研究已证实SIRPα对白细胞炎症反应的负调节作用以及微小核糖核酸对巨噬细胞SIRPα的转录后调控的基础上，我们近期工作又发现SIRPα能抑制巨噬细胞M2型丙酮酸激酶(PKM2)的磷酸化，从而下调炎症诱导的巨噬细胞的有氧糖酵解(Warburg效应)，抑制巨噬细胞促炎型M1极化和机体炎症反应。本项目将在此基础上，利用成功获得的SIRPα敲基因鼠进一步研究SIRPα调控巨噬细胞有氧糖酵解和炎症反应的机制。本研究将有助于更全面地认识巨噬细胞功能及炎症相关疾病，并为临床防治炎症相关疾病提供新的靶点。

大量研究表明白细胞特有的信号调节蛋白(SIRPα)对巨噬细胞炎症反应有重要调节作用，但其分子机制还不清楚。我们的研究阐明了SIRPα调控巨噬细胞炎症反应和天然免疫的作用机制。首先，我们证实了SIRPα对白细胞炎症反应的负调节作用；进一步地，我们进一步发现SIRPα能抑制M2型丙酮酸激酶(PKM2)的磷酸化，从而下调炎症诱导的巨噬细胞的有氧糖酵解(Warburg效应)，抑制巨噬细胞促炎型M1极化和机体炎症反应；此基础上，我们利用成功获得的SIRPαITIM删除和SIRPα敲基因鼠进一步证实了SIRPα通过调节PKM2的磷酸化水平调控巨噬细胞有氧糖酵解和炎症反应的作用和机制。本研究将有助于更全面地认识巨噬细胞功能及炎症相关疾病，并为临床防治炎症相关疾病提供新的靶点。