The miR-126/VEGFR2 axis controls the innate response to pathogen-associated nucleic acids

microRNA-126 is a microRNA predominately expressed by endothelial cells and controls angiogenesis. Unexpectedly, we found that mice deficient in miR-126 have a major impairment in their innate response to pathogen-associated nucleic acids, as well as HIV, which results in more widespread cell infection. Further examination revealed that this was due to miR-126 control of plasmacytoid DC (pDC) homeostasis and function, and that miR-126 regulates expression of TLR7, TLR9, NFkB1 and other innate response genes, as well as VEGF-receptor 2 (VEGFR2). Deletion of VEGFR2 on DCs resulted in reduced interferon production, supporting a role for VEGFR2 in miR-126 regulation of pDCs. These studies identify the miR-126/VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs. Plasmactyoid dendritic cells were FACS-sorted from spleens from wildtype and miR-126 KO mice and their RNA extracted. RNA was amplified, labeled and hybridized to Mouse Gene 1.0 ST arrays with the data generation and quality control pipeline of 19 the Immunological Genome Project (www.immgen.org). Raw data were background-corrected and normalized using the RMA algorithm.

微小RNA-126（microRNA-126）是一类主要由内皮细胞表达的微小RNA，可调控血管生成。令人意外的是，本研究发现miR-126缺陷小鼠在应对病原体相关核酸以及人类免疫缺陷病毒（HIV）的天然免疫应答中存在显著缺陷，进而导致更广泛的细胞感染。进一步研究表明，该现象源于miR-126对浆细胞样树突状细胞（plasmacytoid dendritic cell, pDC）稳态与功能的调控；同时miR-126可调控Toll样受体7（TLR7）、Toll样受体9（TLR9）、核因子κB1（NFκB1）以及其他天然免疫应答相关基因与血管内皮生长因子受体2（vascular endothelial growth factor receptor 2, VEGFR2）的表达。树突状细胞（dendritic cell, DC）上VEGFR2的敲除会导致干扰素生成减少，这为VEGFR2参与miR-126对pDC的调控提供了佐证。本研究证实miR-126/VEGFR2信号轴是通过多维度调控pDC来发挥天然免疫应答调控作用的重要通路。研究人员从野生型与miR-126基因敲除（knockout, KO）小鼠的脾脏中通过荧光激活细胞分选（fluorescence-activated cell sorting, FACS）得到浆细胞样树突状细胞，并提取其RNA。将RNA进行扩增、标记后，与小鼠基因1.0 ST芯片（Mouse Gene 1.0 ST arrays）进行杂交，实验数据的生成与质量控制流程遵循免疫基因组计划（Immunological Genome Project, ImmGen；www.immgen.org）的标准规范。原始数据通过RMA算法进行背景校正与标准化处理。