Long noncoding RNAs (lncRNAs) play an indispensable role in the process of M1 macrophage via regulating the development of macrophages and their responses to bacterial pathogens and viral infections. However, there are few studies on the lncRNA-mediated functions and regulatory mechanisms of M2 macrophage polarization. In this study, we found a number of differentially expressed lncRNAs between human monocyte derived M0 and M2 macrophages according to array analysis and quantitative polymerase chain reaction (qPCR) validation. The lncRNA RP11−389C8.2 (we named lnc-M2 in this study) was observed to be highly expressed in M2 macrophages. In Situ Localization and Quantification Analysis showed that lnc-M2 was expressed in the nucleus and cytosolic compartments of M2 macrophages. Notably, lnc-M2 knockdown enhanced the phagocytic ability of M2 macrophages. Ulteriorly, the results of RNA-Protein interaction experiments indicated that protein kinase A (PKA) was a lnc-M2 associated RNA-binding protein (RBP). Western blot showed that phosphorylated cAMP response element binding protein (p-CREB), a well-known key downstream transcription factor of PKA, was lowly phosphorylated in lnc-M2-silencing M2 macrophages. Furthermore, we found that transcriptional factor Signal Transducer And Activator Of Transcription 3 (STAT3) promoted lnc-M2 transcription along with the up-regulation of epigenetic histone modification markers at the lnc-M2 promoter locus, indicating that STAT3 activated lnc-M2 and eventually facilitated the process of M2 macrophage differentiation via the PKA/CREB pathway. Collectively, our date provide evidence that the transcription factor STAT3 can promote the transcription of lnc-M2 and facilitated the process of M2 macrophage differentiation via the PKA/CREB pathway. This study highlights a novel mechanism underlying the M2 macrophage differentiation.

长非编码RNA（lncRNA）通过调节巨噬细胞的发育及其对细菌病原体和病毒感染的反应，在M1巨噬细胞的过程中起着不可或缺的作用。然而，关于lncRNA介导的M2巨噬细胞极化的功能和调控机制的研究很少。在这项研究中，我们通过阵列分析和定量聚合酶链反应（qPCR）验证，在人单核细胞衍生的M0和M2巨噬细胞之间发现了许多差异表达的lncRNA。观察到lncRNA RP11-389C8.2（在本研究中我们称为lnc-M2）在M2巨噬细胞中高度表达。原位定位和定量分析表明lnc-M2在M2巨噬细胞的细胞核和胞质区室表达。值得注意的是 lnc-M2敲低增强了M2巨噬细胞的吞噬能力。RNA-蛋白质相互作用实验的结果表明，蛋白激酶A（PKA）是lnc-M2相关的RNA结合蛋白（RBP）。蛋白质印迹表明，磷酸化的cAMP反应元件结合蛋白（p-CREB）是PKA众所周知的关键下游转录因子，在lnc-M2沉默的M2巨噬细胞中磷酸化程度较低。此外，我们发现转录因子信号转导子和转录激活因子3（STAT3）促进了lnc-M2转录，并在lnc-M2启动子位点上调了表观遗传组蛋白修饰标记，表明STAT3激活了lnc-M2，并最终激活了通过PKA / CREB途径促进了M2巨噬细胞的分化过程。总的来说，我们的日期提供了证据，表明转录因子STAT3可以通过PKA / CREB途径促进lnc-M2的转录并促进M2巨噬细胞的分化过程。这项研究突出了潜在的M2巨噬细胞分化的新机制。