INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway.
INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway.
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INT-HA 通过 TLR4-miR-935 途径诱导人单核细胞的 M2 样巨噬细胞分化。
DOI：
10.1007/s00262-018-2261-6
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Gao Feng
中科院分区：
文献类型：
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作者：
Zhang Boke;Du Yan;He Yiqing;Liu Yiwen;Zhang Guoliang;Yang Cuixia;Gao Feng
肿瘤相关巨噬细胞（tumor-associated macrophages，TAM）是实体瘤微环境的主要组成部分，促进肿瘤的进展。中等大小的透明质酸（INT-HA）片段在细胞分化中具有免疫功能;然而，它们在促进非活化巨噬细胞极化为M2样TAM表型中的作用尚未得到表征，并且潜在的机制仍不清楚。在这里，我们使用miRNA微阵列发现一些miRNA（特别是miR-935）在INT-HA诱导的M2样巨噬细胞中受到差异调节。RT-qPCR和Western blot结果显示，miR-935与控制巨噬细胞极化的C/EBPβ之间存在相关性。此外，我们发现INT-HA通过TLR 4受体诱导M2样表型。在我们的研究中，实体瘤患者外周血单核细胞中的血浆HA和miR-935之间存在负相关性。单核细胞中miR-935和M2样巨噬细胞标志物之间也存在负相关。这些发现表明HA片段与TLR 4相互作用并通过miR-935将巨噬细胞极化为M2样表型。因此，这项研究为miR-935在INT-HA诱导的M2样极化中的作用提供了新的见解，并提出了抗肿瘤治疗的潜在治疗靶点。
As a major component of the microenvironment of solid tumors, tumor-associated macrophages (TAMs) facilitate tumor progression. Intermediate-sized hyaluronan (INT-HA) fragments have an immunological function in cell differentiation; however, their role in promoting the polarization of non-activated macrophages to an M2-like TAM phenotype has not been characterized, and the underlying mechanisms remain unclear. Here, we used a miRNA microarray to find that some miRNAs (especially miR-935) were differentially regulated in INT-HA-induced M2-like macrophages. According to RT-qPCR and Western blot, there was an association between miR-935 and C/EBPβ, that control the polarization of macrophages. Moreover, we found that INT-HA induced an M2-like phenotype via the TLR4 receptor. In our study, there was a negative correlation between plasma HA and miR-935 in monocytes from the peripheral blood of patients with solid tumors. There was also a negative correlation between miR-935 and M2-like macrophage markers in monocytes. These findings suggest that HA fragments interact with TLR4 and educate macrophage polarization to an M2-like phenotype via miR-935. Therefore, this study provides new insight into the role of miR-935 in INT-HA-induced M2-like polarization, and suggests a potential therapeutic target for antitumor treatment.