LncRNA MALAT1/microRNA-30b axis regulates macrophage polarization and function.
LncRNA MALAT1/microRNA-30b axis regulates macrophage polarization and function.
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DOI：
10.3389/fimmu.2023.1214810
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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巨噬细胞（Mφ）是长寿的髓系细胞，可朝促炎的M1型或促消退的M2型极化，以控制诸如炎症、组织损伤和再生等多种生物学过程。非编码RNA是一类不编码蛋白质的转录组，具有众多相互依赖的生物学作用；然而，它们在巨噬细胞极化和免疫应答调节中的功能相互作用仍不清楚。在此，我们展示了长链非编码RNA（MALAT1）和微小RNA（miR - 30b）在塑造巨噬细胞极化和免疫功能方面的拮抗关系。MALAT1的表达在巨噬细胞分化过程中以及受到Toll样受体4激动剂（大肠杆菌脂多糖）刺激时呈现出时间依赖性诱导。MALAT1的敲低促进了M2型巨噬细胞标志物的表达，而不影响M1型巨噬细胞标志物，这表明MALAT1通过抑制M2分化而有利于M1表型。与对照组相比，MALAT1敲低导致抗原摄取和加工、细菌吞噬以及杀菌活性降低，有力地支持了它在调节巨噬细胞固有免疫功能中的关键作用。与此一致的是，MALAT1敲低在受到脂多糖刺激时显示出细胞因子分泌受损。重要的是，在M2型巨噬细胞分化过程中，MALAT1与miR - 30家族的所有五个成员呈现出拮抗表达模式。双荧光素酶实验验证了MALAT1上一个与miR - 30b相互作用的新序列，miR - 30b是一种促进M2表型的微小RNA。吞噬和抗原加工实验明确表明MALAT1和miR - 30b在功能上是拮抗的。同时进行MALAT1敲低和miR - 30b过表达在这两种实验中都表现出最显著的减弱。在患有牙周病的人类受试者以及结扎诱导的牙周炎小鼠模型中，我们观察到牙龈组织中MALAT1水平升高、M1型巨噬细胞标志物增加以及miR - 30b表达下调，这表明MALAT1在体内具有促炎功能。总体而言，我们揭示了MALAT1在巨噬细胞极化中的作用，并通过涉及MALAT1驱动的miR - 30b隔离作用阐述了其调节的潜在机制。
Macrophages (Mφ) are long-lived myeloid cells that can polarize towards the proinflammatory M1 or proresolving M2 phenotype to control diverse biological processes such as inflammation, tissue damage, and regeneration. Noncoding RNA are a class of nonprotein-coding transcriptome with numerous interdependent biological roles; however, their functional interaction in the regulation of Mφ polarization and immune responses remain unclear. Here, we show antagonistic relationship between lncRNA (MALAT1) and microRNA (miR-30b) in shaping macrophage polarization and immune functions. MALAT1 expression displays a time-dependent induction during Mφ differentiation and, upon challenge with TLR4 agonist (E. coli LPS). MALAT1 knockdown promoted the expression of M2Mφ markers without affecting M1Mφ markers, suggesting that MALAT1 favors the M1 phenotype by suppressing M2 differentiation. Compared to the control, MALAT1 knockdown resulted in reduced antigen uptake and processing, bacterial phagocytosis, and bactericidal activity, strongly supporting its critical role in regulating innate immune functions in Mφ. Consistent with this, MALAT1 knockdown showed impaired cytokine secretion upon challenge with LPS. Importantly, MALAT1 exhibit an antagonistic expression pattern with all five members of the miR-30 family during M2 Mφ differentiation. Dual-luciferase assays validated a novel sequence on MALAT1 that interacts with miR-30b, a microRNA that promotes the M2 phenotype. Phagocytosis and antigen processing assays unequivocally demonstrated that MALAT1 and miR-30b are functionally antagonistic. Concurrent MALAT1 knockdown and miR-30b overexpression exhibited the most significant attenuation in both assays. In human subjects with periodontal disease and murine model of ligature-induced periodontitis, we observed higher levels of MALAT1, M1Mφ markers and downregulation of miR-30b expression in gingival tissues suggesting a pro-inflammatory function of MALAT1 in vivo. Overall, we unraveled the role of MALAT1 in Mφ polarization and delineated the underlying mechanism of its regulation by involving MALAT-1-driven miR-30b sequestration.
影响因子：
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作者：
Chen Q;Cao M;Ge H
通讯作者：
Ge H