MicroRNA Let-7 Induces M2 Macrophage Polarization in COPD Emphysema Through the IL-6/STAT3 Pathway

Abstract

Background M2 polarized macrophages are involved in the occurrence and development of emphysema in COPD patients. However, the molecular mechanism of M2 macrophage polarization is still unclear. This study investigated the molecular mechanism of let-7 differentially expressed in bronchial epithelial cells of COPD patients participating in COPD emphysema by regulating the expression of IL-6 and inducing M2 polarization of alveolar macrophages (AM). Materials and Methods We measured let-7c expression in human lung tissue, serum and the lung tissue of cigarette smoke (CS)-exposed mice by qRT‒PCR. We observed the M1/M2 AM polarization in the lungs of COPD patients and COPD model mice by immunofluorescence analysis. Western blotting was used to determine the expression of MMP9/12 in the lung tissue of COPD patients and CS-exposed mice. An in vitro experiment was performed to determine the molecular mechanism of let-7c-induced macrophage polarization. Results Let-7c expression was downregulated in COPD patients, CS-exposed mice, and CS extract (CSE)-treated human bronchial epithelial (HBE) cells. AMs in COPD patients and CS-exposed mice were dominated by the M2 type, and the release of MMP9/12 was increased. In vitro, the transfection of mimics overexpressing let-7 or the use of tocilizumab to block signal transduction between HBE cells and macrophages inhibited the IL-6/STAT3 pathway. M2 macrophage polarization was inhibited, and MMP9/12 release was reduced. Conclusion Our results indicate that CS decreased let-7c expression in HBE cells, and M2 AM polarization was dominant in COPD. In HBE cells, let-7c could inhibit M2 polarization of AMs through the IL-6/STAT3 pathway, providing potential diagnostic and therapeutic value for slowing COPD emphysema.

Macrophage Polarization and Functions in Pathogenesis of Chronic Obstructive Pulmonary Disease

“…For example, the knockout of miR-21, which is increased in the lung tissue and BMDM of the COPD model, showed decreased levels of M2-related genes (CD206, ARG1, YM1, FIZZ1, and IL10) [ 187 ]. The overexpression of microRNA let-7c, which is downregulated in the lungs of patients with COPD, inhibited CSE-induced M2 polarization in vitro by the inhibition of the IL6/STAT3 pathway [ 156 ]. PM2.5 induced M2 macrophage polarization by the inhibition of histone deacetylase 2 (HDAC2).…”

Mechanism of KLF9 in airway inflammation in chronic obstructive pulmonary

“…The preparation of cigarette smoke extract (CSE) was conducted according to the previous report. 21 The smoke from two cigarettes was dissolved in 10 mL serum-free DMEM, forming CSE solution with a 7.4 pH value. Next, CSE solution was filtered through a 0.22-μm pore filter to wipe out insoluble particles and was standardized by absorbance measurement at 320 and 540 nm, which was defined as 100% CSE.…”