MiR-19a-3p Suppresses M1 Macrophage Polarization by Inhibiting STAT1/IRF1 Pathway.

Xiaoxiao Zhu,Zhen Zhang,Xia Li,Lin Zhao,Qiang Guo,Bin Wang,Yunhong Zhang,Chu Chu,Xiaoxiao Fu,Jing Zou,Ran Wei

doi:10.3389/fphar.2021.614044

Abstract

Macrophages, an important type of immune cells, are generally polarized to classically activated macrophage (M1) or alternatively activated macrophage (M2) to respond to environmental stimuli. Signal transducer and activator of transcription 1 (STAT1), a very important transcription factor, can promote M1 macrophage polarization. However, the mechanisms of regulating STAT1 in macrophage polarization remain unclear. In the present study, STAT1 was markedly elevated, however, miR-19a-3p was down-regulated in interferon (IFN)-γ and lipopolysaccharide (LPS) treated RAW264.7 cells, and dual-luciferase reporter assay identified that miR-19a-3p directly targeted STAT1 by binding to its 3′UTR. Up-regulated miR-19a-3p inhibited M1 polarization by targeting STAT1/interferon regulatory factor 1 (IRF1) and vice versa in vitro. Consistently, overexpression of miR-19a-3p in LPS treated mice by systemically administering agomiR-19a-3p effectively reduced the inflammation in mouse lung tissues, and inhibited M1 macrophage polarization via suppressing STAT1/IRF1 pathway. In summary, our study confirmed that miR-19a-3p, as a direct regulator of STAT1, inhibited M1 macrophages polarization. The miR-19a-3p/STAT1/IRF1 pathway can potentially be used to design novel immunotherapy for modulating macrophage polarization.

Highlights

Macrophages, an essential component of innate immunity, have high plasticity and can display divergent phenotypes and functions (Lawrence and Natoli, 2011)
Microarray analysis showed that miR-19a-3p was reduced, while Signal transducer and activator of transcription 1 (STAT1) was increased significantly in M1 macrophages derived from RAW264.7 cells, and miR-19a-3p was negatively correlated with STAT1
The mRNA, protein expression and phosphorylation level of STAT1 were notably elevated in IFN-γ and LPS induced RAW264.7 cells (Figures 1C,D), that were consistent with previous results (Iwata et al, 2016)

Summary

Introduction

Macrophages, an essential component of innate immunity, have high plasticity and can display divergent phenotypes and functions (Lawrence and Natoli, 2011). M1 macrophages play a prominent role in immune surveillance by secreting pro-inflammatory cytokines and chemokines, and high antigen presentation. While M2 macrophages have significant effects in immune regulation by secreting cytokines IL-10 and/or TGF-β which are related to anti-inflammatory effect (Lawrence and Natoli, 2011; Hamilton et al, 2014; Bi et al, 2016; Shapouri-Moghaddam et al, 2018). Many transcription factors play important roles in macrophage polarization, such as interferon regulatory factors (IRFs), nuclear transcription factor-κB (NF-κB), signal transducer and activator of transcriptions (STATs), MiR-19a-3p Inhibits M1 Macrophage Polarization and so on (Lawrence and Natoli, 2011; Glass and Natoli, 2016; Huang et al, 2018; Li et al, 2018; Ma et al, 2018; Larionova et al, 2020a). STAT1 exerts a crucial role in modulating the polarization of macrophages

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Results

Conclusion