Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, United States.
Front Immunol. 2023 Oct 4;14:1214810. doi: 10.3389/fimmu.2023.1214810. eCollection 2023.
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 . 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.
巨噬细胞（Mφ）是寿命较长的髓样细胞，可以向促炎 M1 或促修复 M2 表型极化，以控制多种生物学过程，如炎症、组织损伤和再生。非编码 RNA 是一类非蛋白质编码转录组，具有许多相互依赖的生物学作用；然而，它们在调节 Mφ极化和免疫反应中的功能相互作用尚不清楚。在这里，我们展示了长链非编码 RNA（MALAT1）和 microRNA（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 Mφ分化过程中呈现出时间依赖性诱导，并且在 TLR4 激动剂（大肠杆菌 LPS）刺激下。MALAT1 敲低促进了 M2Mφ 标志物的表达，而不影响 M1Mφ 标志物的表达，表明 MALAT1 通过抑制 M2 分化有利于 M1 表型。与对照组相比，MALAT1 敲低导致抗原摄取和加工、细菌吞噬和杀菌活性减少，强烈支持其在调节 Mφ固有免疫功能中的关键作用。与此一致，MALAT1 敲低在 LPS 刺激下表现出细胞因子分泌减少。重要的是，MALAT1 在 M2 Mφ 分化过程中与 miR-30 家族的所有五个成员表现出拮抗表达模式。双荧光素酶报告基因实验验证了 MALAT1 上与 miR-30b 相互作用的一个新序列，miR-30b 促进 M2 表型。吞噬和抗原处理实验明确证明了 MALAT1 和 miR-30b 具有功能拮抗作用。在这两项实验中，同时敲低 MALAT1 和过表达 miR-30b 表现出最显著的衰减。在牙周病患者和结扎诱导牙周炎的小鼠模型中，我们观察到牙龈组织中 MALAT1、M1Mφ 标志物水平升高和 miR-30b 表达下调，提示 MALAT1 具有促炎功能。总体而言，我们揭示了 MALAT1 在 Mφ 极化中的作用，并通过涉及 MALAT1 驱动的 miR-30b 隔离来描绘其调节的潜在机制。
Zotero 插件
