DataSheet_1_Crosstalk Between LXR and Caveolin-1 Signaling Supports Cholesterol Efflux and Anti-Inflammatory Pathways in Macrophages.pdf

Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis.

巨噬细胞（Macrophages）是一类免疫细胞，通过激活其卓越的吞噬与炎症功能，在宿主抵御病原体的过程中发挥关键作用。定居于健康组织的巨噬细胞还可执行多项重要任务以维持器官稳态，包括脂质摄取/外排或凋亡细胞清除。巨噬细胞的稳态与炎症功能均需要位于细胞膜的富含脂质微结构域保持精准稳定性，以启动下游信号级联反应。小窝蛋白1（Caveolin-1, Cav-1）是介导小窝生物合成的核心蛋白，在血管炎症与动脉粥样硬化中发挥重要作用。肝X受体（Liver X receptors, LXRs）是巨噬细胞中胆固醇外排与炎症基因应答的关键转录因子。此前虽已有研究报道Cav-1在细胞胆固醇稳态及血管炎症中的作用，但LXR转录活性与巨噬细胞中Cav-1表达及功能之间的关联尚未得到探究。本研究通过功能获得与功能缺失实验方法，证实巨噬细胞活化过程中，LXR依赖的转录通路可调控Cav-1的表达及其在细胞膜中的分区分布。据此，Cav-1参与LXR依赖的胆固醇外排过程与炎症应答调控。综上，本研究数据表明，靶向调控LXR-Cav-1轴，或可用于控制脂质与免疫紊乱（如动脉粥样硬化）发病过程中巨噬细胞的过度炎症与胆固醇过载。