MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response

Abstract

Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro-inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed.

Figures

Figure 1. Classical activation of macrophages (M1)

Ligands IFN-γ, LPS and GM-CSF activate STAT1, NF-κB, AP-1, IRFs to stimulate transcription of M1 associated genes.

Figure 2

(A) M2a polarization. Ligands IL-4 and IL-13 activate STAT6/IRF4 signaling pathway to induce M2a phenotype in macrophages. (B) M2b polarization. IL-1R ligands or immune complexes in combination with LPS activate Syc and PI3K to induce transcription of IL-10 and M2b phenotype. (C) M2c polarization. IL-10 and glucocorticoids activate M2c phenotype through STAT, NF-κB and MKP-1 activation.

Figure 3

miRNA expression profile in polarized macrophages, based on the papers by Zhang et al. (28) and by Cobos Jimenez et al. (29). Green: Upregulated miRNAs, Red: Downregulated miRNAs, Black: unknown or unchanged miRNAs.

Figure 4

Diagram illustrates miRNAs that induce either classical activation or alternative activation of macrophages and their corresponding targets.