MicroRNA-451a in extracellular, blood-resident vesicles attenuates macrophage and dendritic cell responses to influenza whole-virus vaccine
MicroRNA-451a in extracellular, blood-resident vesicles attenuates macrophage and dendritic cell responses to influenza whole-virus vaccine
复制标题
DOI：
10.1074/jbc.ra118.003862
复制
发表时间：
2018-11-30
影响因子：
4.8
通讯作者：
Oshiumi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Okamoto, Masaaki;Fukushima, Yoshimi;Oshiumi, Hiroyuki
先天免疫系统对疫苗的效力很重要，但过度的先天免疫反应可能会在接种疫苗后引起不良反应。细胞外小泡(EV)在血液中丰富，可以将功能RNAs，如microRNAs(MiRNAs)运送到受体细胞，从而调节细胞间的通讯。然而，EVS在控制疫苗的先天免疫反应中的作用尚未完全阐明。在这里，我们发现miR-451a在人血清EVS中含量丰富，它在血液循环EVS中的存在影响巨噬细胞和树突状细胞对流感灭活全病毒疫苗(WV)的先天免疫反应。人血清EVS中MIR-451a在健康人血清中稳定一周，并在几个月内逐渐波动。血清EVS中的MIR-451a内化到血清培养的巨噬细胞和树突状细胞中，并降低内源性14-3-3Zeta蛋白水平，并降低WV刺激后I型干扰素和白介素6的表达。血循环EV中的miR-451a水平与小鼠脾CD11c(+)细胞内miR-451a水平呈正相关，与体内灭活WV的天然免疫应答呈负相关。这些发现表明，循环EVS中的miR-451a在体内内化到受体细胞中，这种内化导致对WV的先天免疫反应减弱。此外，微阵列分析还发现了其他几个影响巨噬细胞对灭活的WV反应的miRNAs。我们的结果显示，循环EV中的miR-Nas显著改变巨噬细胞和树突状细胞对灭活WV的反应。
The innate immune system is important for the efficacy of vaccines, but excessive innate immune responses can cause adverse reactions after vaccination. Extracellular vesicles (EVs) are enriched in the blood and can deliver functional RNAs, such as microRNAs (miRNAs), to recipient cells, thereby mediating intercellular communication. However, the role of EVs in controlling the innate immune responses to vaccines has not been fully elucidated. Here, we found that miR-451a is abundant in human serum EVs and that its presence in blood-circulating EVs affects the innate immune responses of macrophages and dendritic cells to inactivated whole-virus vaccines (WV) against influenza. miR-451a in human serum EVs was stable for a week in healthy subjects, and its levels gradually fluctuated over several months. miR-451a within serum EVs was internalized into serum-cultured macrophages and dendritic cells and reduced endogenous 14-3-3 zeta protein levels and decreased the expression of type I IFN and interleukin 6 in response to WV stimulation. miR-451a levels in blood-circulating EVs were positively correlated with intracellular miR-451a levels in mouse splenic CD11c(+) cells and inversely correlated with the innate immune response to inactivated WV in vivo. These findings suggest that miR-451a in circulating EVs is internalized into recipient cells in vivo and that this internalization results in an attenuation of the innate immune response to WV. Moreover, a microarray analysis identified several other miRNAs that affect the macrophage response to inactivated WV. Our results reveal that miR-NAs in circulating EVs significantly modify the responses of macrophages and dendritic cells to inactivated WV.