Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK, USA.
Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, 264 McElroy Hall, Stillwater, OK, 74078, USA.
Sci Rep. 2020 Aug 13;10(1):13672. doi: 10.1038/s41598-020-70633-7.
Macrophages play an essential role in host defense and display remarkable plasticity in switching between classically (pro-inflammatory-M1) and alternatively activated (anti-inflammatory-M2) phenotypes. The molecular mechanisms of macrophage polarization are not fully understood. Long non-coding RNAs (lncRNAs) with a length of > 200 nucleotides have been shown to play diverse roles in biological processes. Aberrant expression of lncRNAs is associated with a variety of pathophysiological conditions such as cancer, diabetes, cardiovascular, pulmonary diseases, and tissue fibrosis. In this study, we investigated the role of lncRNA FENDRR in human and mouse macrophage polarization. Human THP-1 monocytes were activated with phorbol-12-myristate-13-acetate (PMA) and differentiated into M1 macrophages with IFNγ or M2 macrophages with IL4. Real-time PCR analysis revealed that FENDRR was expressed 80-fold higher in M1 macrophages than that in M2 macrophages. Overexpression of FENDRR in PMA-activated THP-1 cells increased the IFNγ-induced expression of M1 markers, including IL1β and TNFα at both mRNA and protein levels. Knockdown of FENDRR had an opposite effect. Similarly, FENDRR overexpression in primary mouse bone marrow-derived macrophages increased mRNA expression of M1 markers. FENDRR overexpression increased, while FENDRR knock-down decreased, the IFNγ-induced phosphorylation of STAT1 in PMA-activated THP-1 cells. Our studies suggest that FENDRR enhances IFNγ-induced M1 macrophage polarization via the STAT1 pathway.
巨噬细胞在宿主防御中发挥着重要作用，并在经典（促炎-M1）和替代激活（抗炎-M2）表型之间表现出显著的可塑性。巨噬细胞极化的分子机制尚未完全阐明。长度超过 200 个核苷酸的长非编码 RNA（lncRNA）已被证明在生物过程中发挥着多种作用。lncRNA 的异常表达与多种病理生理状况有关，如癌症、糖尿病、心血管、肺部疾病和组织纤维化。在这项研究中，我们研究了 lncRNA FENDRR 在人源和鼠源巨噬细胞极化中的作用。人源 THP-1 单核细胞用佛波醇-12-肉豆蔻酸-13-乙酸酯（PMA）激活，并在 IFNγ的作用下分化为 M1 巨噬细胞，或在 IL4 的作用下分化为 M2 巨噬细胞。实时 PCR 分析显示，FENDRR 在 M1 巨噬细胞中的表达水平比 M2 巨噬细胞高 80 倍。在 PMA 激活的 THP-1 细胞中转染 FENDRR 可增加 IFNγ诱导的 M1 标志物（包括 IL1β 和 TNFα）的 mRNA 和蛋白水平表达。FENDRR 的敲低则产生相反的效果。同样，FENDRR 在原代鼠骨髓来源巨噬细胞中的过表达增加了 M1 标志物的 mRNA 表达。FENDRR 的过表达增加了 IFNγ诱导的 PMA 激活的 THP-1 细胞中 STAT1 的磷酸化，而 FENDRR 的敲低则降低了其磷酸化。我们的研究表明，FENDRR 通过 STAT1 通路增强了 IFNγ诱导的 M1 巨噬细胞极化。
