miR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.
miR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.
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miR-148a-3p 介导 notch 信号传导以促进巨噬细胞的分化和 M1 激活
DOI：
10.3389/fimmu.2017.01327
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发表时间：
2017
影响因子：
7.3
通讯作者：
Qin HY
中科院分区：
文献类型：
--
作者：
Huang F;Zhao JL;Wang L;Gao CC;Liang SQ;An DJ;Bai J;Chen Y;Han H;Qin HY
Notch通路在巨噬细胞的分化和极化活化中起关键作用;然而，巨噬细胞中Notch活性的下游分子机制仍然难以捉摸。我们先前的研究已经鉴定了一组介导Notch信号传导以调节巨噬细胞活化和肿瘤相关巨噬细胞（TAMs）的microRNA。在这项研究中，我们证明了miR-148 a-3 p作为一种新型的Notch信号下游分子，在粒细胞巨噬细胞集落刺激因子（GM-CSF）的存在下促进单核细胞分化为巨噬细胞。同时，miR-148 a-3 p促进Notch激活后巨噬细胞的M1极化，抑制M2极化。过表达miR-148 a-3 p的巨噬细胞吞噬和杀死细菌的能力增强，这是由过量产生活性氧（ROS）介导的。使用报告基因分析和蛋白质印迹的进一步研究将Pten鉴定为巨噬细胞中miR-148 a-3 p的直接靶基因。过表达miR-148 a-3 p的巨噬细胞通过PTEN/AKT途径增加其ROS产生，可能防御细菌入侵。此外，miR-148 a-3 p还通过PTEN/AKT介导的NF-κB信号转导上调增强M1巨噬细胞极化和促炎反应。总之，我们的数据建立了一种新的分子机制，Notch信号通过miR-148 a-3 p促进单核细胞分化和M1巨噬细胞活化，并表明miR-148 a-3 p修饰的单核细胞或巨噬细胞是治疗炎症相关疾病的潜在新工具。
The Notch pathway plays critical roles in the differentiation and polarized activation of macrophages; however, the downstream molecular mechanisms underlying Notch activity in macrophages remain elusive. Our previous study has identified a group of microRNAs that mediate Notch signaling to regulate macrophage activation and tumor-associated macrophages (TAMs). In this study, we demonstrated that miR-148a-3p functions as a novel downstream molecule of Notch signaling to promote the differentiation of monocytes into macrophages in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF). Meanwhile, miR-148a-3p promoted M1 and inhibited M2 polarization of macrophages upon Notch activation. Macrophages overexpressing miR-148a-3p exhibited enhanced ability to engulf and kill bacteria, which was mediated by excessive production of reactive oxygen species (ROS). Further studies using reporter assay and Western blotting identified Pten as a direct target gene of miR-148a-3p in macrophages. Macrophages overexpressing miR-148a-3p increased their ROS production through the PTEN/AKT pathway, likely to defend against bacterial invasion. Moreover, miR-148a-3p also enhanced M1 macrophage polarization and pro-inflammatory responses through PTEN/AKT-mediated upregulation of NF-κB signaling. In summary, our data establish a novel molecular mechanism by which Notch signaling promotes monocyte differentiation and M1 macrophage activation through miR-148a-3p, and suggest that miR-148a-3p-modified monocytes or macrophages are potential new tools for the treatment of inflammation-related diseases.
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影响因子：
30.5
作者：
Gonzalez-Martin A;Adams BD;Lai M;Shepherd J;Salvador-Bernaldez M;Salvador JM;Lu J;Nemazee D;Xiao C
通讯作者：
Xiao C
影响因子：
4.7
作者：
Carnero A;Paramio JM
通讯作者：
Paramio JM
影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
影响因子：
4.4
作者：
Monsalve, Eva;Perez, Miguel A.;Diaz-Guerra, Maria Jose M.
通讯作者：
Diaz-Guerra, Maria Jose M.
影响因子：
4.4
作者：
Han, H;Tanigaki, K;Honjo, T
通讯作者：
Honjo, T