The circRERE/miR-144-3p/TLR2/MMP9 signaling axis in COPD pulmonary monocytes promotes the EMT of pulmonary epithelial cells

Li, Yongqiang; Lü, Xing; Liu, Weifeng; Shi, Zhipeng; Du, Wei; Xu, Hong; Liu, Zhifeng; Wu, Yuting

doi:10.1016/j.bbrc.2022.07.119

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…The secretion profiles of activated macrophages, notably MMP9 and TGF-β, underscore their contribution to COPD pathology. MMP9, secreted by macrophages, has been identified as an independent risk factor for COPD, and it plays a pivotal role in the process of alveolar injury [ 43 , 54 ]. TGF-β was commonly recognized as a classic pro-fibrotic cytokine, and fibrosis was a universal process in airway remodeling.…”

Section: Discussionmentioning

confidence: 99%

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Dong,

Zhu

et al. 2024

Cell Commun Signal

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Background Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C–C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. Methods This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. Results Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. Conclusions The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Dong,

Zhu

et al. 2024

Cell Commun Signal

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“…Це корелювало із курінням сигарет та обструкцією повітряного потоку в пацієнтів із ХОЗЛ, що показано в роботах інших авторів. Так, встановили концентрації MMП-9 і його інгібітора TIMП-1 за допомогою імуноферментного аналізу [17]. Кореля- [18].…”

Section: обговоренняunclassified

Imbalance of the protease-antiprotease system against the background of chronic obstructive pulmonary disease in combination with ischemic heart disease

Kraidashenko

2023

Patologìâ

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The aim of the study: to evaluate the clinical value of the violation of the expression level of MMP-9 and TIMP against the background of chronic obstructive pulmonary disease (COPD) in combination with ischemic heart disease (IHD). Materials and methods. In accordance with the set goal of the study, 26 people with COPD + IHD and 22 practically healthy people were under observation. The average age of patients was 56.68 ± 1.21 years; 76.92 % were men. In the control group, the average age was 54.37 ± 1.84 years, 72.73 % were men. The object of the study was ischemic heart disease: angina pectoris. Research methods: external respiration function study, six minute walk test, determination of heart rate variability, the concentration of MMP-9 and TIMP in blood serum was determined by the method of solid-phase enzyme immunoassay. Results. The analysis of the level of expression of proteases and its inhibitor shows that patients with comorbid IHD on the background of COPD demonstrated 8.11 times higher activity of MMP-9 (p < 0.05) compared to a cohort of practically healthy people. Indicators of TIMP activity in patients with IHD on the background of COPD are 1.46 ± 0.03 μg/ml, which is statistically significantly lower by 53.21 % (p < 0.05) compared to healthy people (3.12 ± 0.01 μg/ml). The presence of reliable correlations between the MMP-9 level and the FEV1 indicator (r = -0.67, p < 0.05), the LF/HF parameter (r = -0.74, p < 0.05) indicates, that when the level of expression of MMP-9 is elevated, there is a more pronounced violation of the function of external respiration and a shift in the sympatho-parasympathetic balance in the direction of sympathetic activation and a decrease in vagal tone in heart rate modulation. The analysis of the meeting frequency with the analysis of conjugation tables showed that in persons in the upper quartile of MMP-9, prognostically negative parameters of the function of external breathing – an isolated decrease in the Tifno index (χ2 = 5.2 at p = 0.03), as well as the expressiveness of shortness of breath – were recorded more often ≥6 points on the Borg scale when assessing exercise tolerance during the 6-minute walk test (χ2 = 7.3 at p = 0.02). Conclusions. The obtained data demonstrate that patients with IHD on the background of COPD have a pronounced proteolytic imbalance and disruption of fibrotic processes compared to practically healthy individuals.

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“…It has been found that activation of the matrix metalloproteinase-9 (MMP-9) gene leads to continuous deterioration of airway remodeling and airway obstruction, which has been confirmed by many researchers. 16–18 Although we know that macrophage polarization is involved in COPD emphysema, the effect of macrophage polarization on the pathogenesis of COPD is still unclear and needs further study.…”

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Zhang²,

Shen³

et al. 2023

COPD

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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.

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The circRERE/miR-144-3p/TLR2/MMP9 signaling axis in COPD pulmonary monocytes promotes the EMT of pulmonary epithelial cells

Cited by 6 publications

References 34 publications

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Imbalance of the protease-antiprotease system against the background of chronic obstructive pulmonary disease in combination with ischemic heart disease

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

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