A18652 Kallikrein-1 Overexpression Alleviates Age-associated Cardiac Fibrosis Through Alternatively Regulating Activated Macrophage Polarization

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

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Rapamycin and FTY720 Alleviate Atherosclerosis by Cross Talk of Macrophage Polarization and Autophagy

BioMed Research International ◽

10.1155/2018/1010248 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Rui-zhen Sun ◽

Ying Fan ◽

Xiao Liang ◽

Tian-tian Gong ◽

Qi Wang ◽

...

Keyword(s):

Lipid Accumulation ◽

Macrophage Polarization ◽

Foam Cells ◽

Peritoneal Macrophages ◽

Macrophage Phenotype ◽

Activated Macrophages ◽

Activated Macrophage ◽

Phenotype Markers ◽

Alternatively Activated ◽

Classically Activated

Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-)β, arginase 1 (Arg1), and mannose receptor C-type 1 (Mrc1) were decreased by rapamycin in peritoneal macrophages. LC3-II was also obviously enhanced, though polarization markers were unchanged in rapamycin-treated foam cells. Moreover, lipid accumulation was inhibited in rapamycin-treated macrophage cells but was unchanged in rapamycin-treated foam cells. For FTY720, LC3-II did not change, whereas TGF-β, Arg1 and Mrc1 were augmented, and IL-6 was suppressed in macrophages. However, LC3-II was increased, and TGF-β, ARG1 and MRC1 were strikingly augmented, whereas IL-6, COX2 and iNOS could be suppressed in foam cells. Furthermore, lipid accumulation was alleviated in FTY720-treated foam cells. Additionally, S1pr1 was markedly decreased in foam cells (P< .05); S1pr2, S1pr3, S1pr4 and S1pr5 were unchanged in rapamycin-treated foam cells. In FTY720-treated foam cells, S1pr3 and S1pr4 were decreased, and S1pr1, S1pr2 and S1pr5 were unchanged. Therefore, we deduced that rapamycin stimulated classically activated macrophages and supressed early atherosclerosis. Rapamycin may also stabilize artery plaques by preventing apoptosis and S1PR1 in advanced atherosclerosis. FTY720 allowed transformation of foam cells into alternatively activated macrophages through the autophagy pathway to alleviate advanced atherosclerosis.

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Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2017.01.035 ◽

2017 ◽

Vol 104 ◽

pp. 298-310 ◽

Cited By ~ 117

Author(s):

Tsung-Ming Lee ◽

Nen-Chung Chang ◽

Shinn-Zong Lin

Keyword(s):

Cardiac Fibrosis ◽

Macrophage Polarization ◽

Sglt2 Inhibitor ◽

Stat3 Signaling ◽

Rat Hearts

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.614044 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoxiao Zhu ◽

Qiang Guo ◽

Jing Zou ◽

Bin Wang ◽

Zhen Zhang ◽

...

Keyword(s):

Macrophage Polarization ◽

Luciferase Reporter ◽

Mouse Lung ◽

Interferon Regulatory Factor 1 ◽

Macrophages Polarization ◽

M1 Polarization ◽

M1 Macrophage ◽

Activated Macrophage ◽

Alternatively Activated

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.

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Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation

Journal of Immunology Research ◽

10.1155/2020/8263598 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Hui Liao ◽

Yuanping Li ◽

Xilan Zhang ◽

Xiaoyun Zhao ◽

Dan Zheng ◽

...

Keyword(s):

High Glucose ◽

Macrophage Polarization ◽

Mannose Receptor ◽

Raw 264.7 Cells ◽

Protective Effects ◽

Activated Macrophages ◽

Podocyte Injury ◽

Protein Expressions ◽

Activated Macrophage

Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1β levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p<0.05). Tha 200 μg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p<0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1β levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p<0.05). The (Tha 200 μg/ml) MS group exhibited a decrease in TNF-α and IL-1β level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p<0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1β levels via its modulation on M1/M2 differentiation.

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Attenuation of Atherosclerosis by Protocatechuic Acid via Inhibition of M1 and Promotion of M2 Macrophage Polarization (P04-063-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz051.p04-063-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Yao Liu ◽

Ling Wenhua

Keyword(s):

Bone Marrow ◽

Protocatechuic Acid ◽

Macrophage Polarization ◽

High Cholesterol Diet ◽

Mouse Bone Marrow ◽

Cholesterol Diet ◽

High Cholesterol ◽

M1 Polarization ◽

Activated Macrophage ◽

J774 Cells

Abstract Objectives Macrophage polarization has a vital impact on the progression of atherosclerosis (AS). Protocatechuic acid (PCA), a flavonol, displays notable atheroprotective effects, but its mechanisms have not been clearly defined. Therefore, we investigated whether PCA attenuated AS by regulating macrophage polarization. Methods Male apolipoprotein E-deficient (ApoE−/−) mice fed a normal chow diet (NCD), a high-cholesterol diet (HCD) or a high-cholesterol diet with PCA (PCA, 15 mg/kg body weight) for 14 weeks. In in vitro studies, mouse-macrophage cell line (J774 cells) and mouse-bone-marrow-derived macrophages (BMDMs) were stimulated with interferon γ (IFN γ) plus lipopolysaccharide (LPS) or interleukin 4 (IL-4) with or without pretreated with PCA for 24 h. Flow cytometry analysis, immunofluorescence, real-time quantitative reverse transcriptase and western blotting were performed for the next measurement. Results PCA consumption inhibited HCD-induced plaque formation (17.84% and 8.21% in the HCD and HCD with PCA groups, respectively; P < 0.05) and inflammatory responses in apolipoprotein E-deficient (ApoE−/−) mice (Fig. 1). Moreover, PCA suppressed the classically activated macrophage (M1) polarization, which decreased the secretion of synthesis of nitric oxide synthase (54.63% and 32.86% in the HCD and HCD with PCA group, respectively; P < 0.05) and proinflammatory factors (Fig. 2). PCA promoted alternatively activated macrophage (M2) activation, which increased the expression of arginine I (6.97% and 26.19% in the HCD and HCD + PCA group, respectively; P < 0.001) and anti-inflammatory factors (Fig. 2). PCA also regulated M1-M2 polarization in J774 cells and mouse-bone-marrow-derived macrophages. Finally, PCA reduced PI3K-Akt-mediated nuclear-factor-κB activation, thereby suppressing M1 polarization, and provoked signal-transducers-and-activators-of-transcription-6 phosphorylation and peroxisome-proliferator-activated-receptor-γ activation, leading to enhanced M2 activation. Conclusions Our data revealed that PCA alleviated AS progression by suppressing M1 polarization and promoting M2 activation. Funding Sources This work was received funding from the Major Projects of Guangzhou Health Collaborative Innovation, the State Key Program of National Natural Science Foundation of China and the Guangdong Science and Technology Project. Supporting Tables, Images and/or Graphs

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YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction

PLoS Biology ◽

10.1371/journal.pbio.3000941 ◽

2020 ◽

Vol 18 (12) ◽

pp. e3000941

Author(s):

Masum M. Mia ◽

Dasan Mary Cibi ◽

Siti Aishah Binte Abdul Ghani ◽

Weihua Song ◽

Nicole Tee ◽

...

Keyword(s):

Myocardial Infarction ◽

Inflammatory Response ◽

Cardiac Function ◽

Cardiac Fibrosis ◽

Macrophage Polarization ◽

Myocardial Damage ◽

Binding Motif ◽

Hippo Signaling ◽

Macrophage Phenotype ◽

Functional Changes

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

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