Abstract
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.
Highlights
Macrophages play a central role in inflammation and host defense and are an essential component of innate immunity[1]
IFNγ increased the mRNA expression of the M1 marker, TNFα and IL1β at 48 h and IL6 at 24 h compared to controls at the same time points (Fig. 1A–C)
We observed that the THP-1 macrophages that polarized toward different phenotypes exhibited dramatic changes in cell shape: IL4-induced M2 cells had a rounded shape with elongated filopodia, while IFNγ-induced M1 cells adopted an elongated, spindle-shaped cell morphology (Fig. 1F)
Summary
Macrophages play a central role in inflammation and host defense and are an essential component of innate immunity[1]. The molecular regulatory mechanisms controlling the expression of specific genes involved in macrophage polarization are not fully clear. Long non-coding RNAs (lncRNAs) play essential roles in many cellular and developmental processes, including cell proliferation, apoptosis, and differentiation as well as organ morphogenesis[11,12]. Deregulated lncRNAs in polarized macrophages are mainly located in intergenic regions (50%), followed by antisense to protein-coding genes (35%). Fetal-lethal non-coding developmental regulatory RNA (FENDRR) is an intergenic lncRNA. Mouse Fendrr is a 2,380 bp transcript consisting of six exons It is transcribed from a bidirectional promoter shared with the protein coding gene Foxf1a, located 1,354 bp from its transcriptional start site. Fendrr acts by modifying the chromatin signatures of genes involved in the formation and differentiation of the lateral mesoderm lineage through binding the PRC2 and Trithorax group/MLL (TrxG/ MLL) complexes[18]. PRC2 catalyzes the methylation of histone H3 at lysine 27 (H3K27me3), which is repressive to gene activity, while the TrxG/MLL complex catalyzes the methylation of histone H3 at lysine 4 (H3K4me3), which acts as an activating m ark[19,20]
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