美国范德堡大学医学中心Kasey C. Vickers和阿肯色大学Ryan M. Allen研究组合作取得一项新成果。他们发现微生物小RNA的LDL递送通过巨噬细胞TLR8诱导动脉粥样硬化。相关论文于2022年12月6日发表在《自然-细胞生物学》杂志上。

研究人员发现微生物小RNA（msRNA）富集在低密度脂蛋白（LDL）上，并通过激活RNA传感器Toll样受体8（TLR8）来诱导促炎巨噬细胞的极化和细胞因子分泌。在LDL重组过程中去除msRNA会产生容易促进甾醇负载但不能诱导炎症激活的颗粒。通过单细胞RNA测序，研究发现TLR8与非靶向锁定核酸的竞争性拮抗可防止天然LDL诱导的体外巨噬细胞极化，并在体内重现病变巨噬细胞表型。至关重要的是，这与不同动脉粥样硬化小鼠模型中的疾病负荷减轻有关。这些结果表明LDL-msRNA是动脉粥样硬化相关炎症的诱导者，揭示了LDL在胆固醇转运以外的其他功能。

据介绍，巨噬细胞具有一系列表型并调控动脉粥样硬化病变的产生和消退。炎性巨噬细胞会促动脉粥样硬化，但仍然不清楚促进这些表型的刺激因子。

附：英文原文

Title: LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8

Author: Allen, Ryan M., Michell, Danielle L., Cavnar, Ashley B., Zhu, Wanying, Makhijani, Neil, Contreras, Danielle M., Raby, Chase A., Semler, Elizabeth M., DeJulius, Carlisle, Castleberry, Mark, Zhang, Youmin, Ramirez-Solano, Marisol, Zhao, Shilin, Duvall, Craig, Doran, Amanda C., Sheng, Quanhu, Linton, MacRae F., Vickers, Kasey C.

Issue&Volume: 2022-12-06

Abstract: Macrophages present a spectrum of phenotypes that mediate both the pathogenesis and resolution of atherosclerotic lesions. Inflammatory macrophage phenotypes are pro-atherogenic, but the stimulatory factors that promote these phenotypes remain incompletely defined. Here we demonstrate that microbial small RNAs (msRNA) are enriched on low-density lipoprotein (LDL) and drive pro-inflammatory macrophage polarization and cytokine secretion via activation of the RNA sensor toll-like receptor 8 (TLR8). Removal of msRNA cargo during LDL re-constitution yields particles that readily promote sterol loading but fail to stimulate inflammatory activation. Competitive antagonism of TLR8 with non-targeting locked nucleic acids was found to prevent native LDL-induced macrophage polarization in vitro, and re-organize lesion macrophage phenotypes in vivo, as determined by single-cell RNA sequencing. Critically, this was associated with reduced disease burden in distinct mouse models of atherosclerosis. These results identify LDL-msRNA as instigators of atherosclerosis-associated inflammation and support alternative functions of LDL beyond cholesterol transport.

DOI: 10.1038/s41556-022-01030-7

Source: https://www.nature.com/articles/s41556-022-01030-7