IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

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STAT6 Deficiency Attenuates Myeloid Fibroblast Activation and Macrophage Polarization in Experimental Folic Acid Nephropathy

Cells ◽

10.3390/cells10113057 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3057

Author(s):

Baihai Jiao ◽

Changlong An ◽

Hao Du ◽

Melanie Tran ◽

Penghua Wang ◽

...

Keyword(s):

Folic Acid ◽

Kidney Disease ◽

Knockout Mice ◽

Renal Fibrosis ◽

Matrix Protein ◽

Macrophage Polarization ◽

Extracellular Matrix Protein ◽

M2 Macrophage ◽

Fibroblast Activation ◽

M2 Macrophage Polarization

Renal fibrosis is a pathologic feature of chronic kidney disease, which can lead to end-stage kidney disease. Myeloid fibroblasts play a central role in the pathogenesis of renal fibrosis. However, the molecular mechanisms pertaining to myeloid fibroblast activation remain to be elucidated. In the present study, we examine the role of signal transducer and activator of transcription 6 (STAT6) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a mouse model of folic acid nephropathy. STAT6 is activated in the kidney with folic acid nephropathy. Compared with folic-acid-treated wild-type mice, STAT6 knockout mice had markedly reduced myeloid fibroblasts and myofibroblasts in the kidney with folic acid nephropathy. Furthermore, STAT6 knockout mice exhibited significantly less CD206 and PDGFR-β dual-positive fibroblast accumulation and M2 macrophage polarization in the kidney with folic acid nephropathy. Consistent with these findings, STAT6 knockout mice produced less extracellular matrix protein, exhibited less severe interstitial fibrosis, and preserved kidney function in folic acid nephropathy. Taken together, these results have shown that STAT6 plays a critical role in myeloid fibroblasts activation, M2 macrophage polarization, extracellular matrix protein production, and renal fibrosis development in folic acid nephropathy. Therefore, targeting STAT6 may provide a novel therapeutic strategy for fibrotic kidney disease.

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Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization

Cardiovascular Research ◽

10.1093/cvr/cvy244 ◽

2018 ◽

Vol 115 (3) ◽

pp. 614-624 ◽

Cited By ~ 12

Author(s):

Taizo Kimura ◽

Kazuko Tajiri ◽

Akira Sato ◽

Satoshi Sakai ◽

Zheng Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Matrix Protein ◽

Molecular Mechanisms ◽

Macrophage Polarization ◽

Left Ventricular ◽

Extracellular Matrix Protein ◽

M2 Macrophage ◽

Ventricular Remodelling ◽

Tenascin C ◽

M2 Macrophage Polarization

Abstract Aims Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. Methods and results MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. Conclusion These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

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Sodium Lactate Accelerates M2 Macrophage Polarization and Improves Cardiac Function after Myocardial Infarction in Mice

Cardiovascular Therapeutics ◽

10.1155/2021/5530541 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Jialiang Zhang ◽

Fangyang Huang ◽

Li Chen ◽

Guoyong Li ◽

Wenhua Lei ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Cardiac Fibrosis ◽

Macrophage Polarization ◽

Flow Cytometric Analysis ◽

Sodium Lactate ◽

M2 Macrophage ◽

Mrna Levels ◽

M2 Macrophage Polarization ◽

Anti Inflammatory

Background. After myocardial infarction, anti-inflammatory macrophages perform key homeostatic functions that facilitate cardiac recovery and remodeling. Several studies have shown that lactate may serve as a modifier that influences phenotype of macrophage. However, the therapeutic role of sodium lactate in myocardial infarction (MI) is unclear. Methods. MI was established by permanent ligation of the left anterior descending coronary artery followed by injection of saline or sodium lactate. Cardiac function was assessed by echocardiography. The cardiac fibrosis area was assessed by Masson trichrome staining. Macrophage phenotype was detected via qPCR, flow cytometry, and immunofluorescence. Signaling proteins were measured by Western blotting. Results. Sodium lactate treatment following MI improved cardiac performance, enhanced anti-inflammatory macrophage proportion, reduced cardiac myocytes apoptosis, and increased neovascularization. Flow-cytometric analysis results reported that sodium lactate repressed the number of the IL-6+, IL-12+, and TNF-α+ macrophages among LPS-stimulated bone marrow-derived macrophages (BMDMs) and increased the mRNA levels of Arg-1, YM1, TGF-β, and IL-10. Mechanistic studies revealed that sodium lactate enhanced the expression of P-STAT3. Furthermore, a STAT3 inhibitor eliminated sodium lactate-mediated promotion macrophage polarization. Conclusion. Sodium lactate facilitates anti-inflammatory M2 macrophage polarization and protects against MI by regulating P-STAT3.

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Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization

The Journals of Gerontology Series A ◽

10.1093/gerona/glv034 ◽

2015 ◽

Vol 71 (4) ◽

pp. 475-483 ◽

Cited By ~ 39

Author(s):

Andriy Yabluchanskiy ◽

Yonggang Ma ◽

Kristine Y. DeLeon-Pennell ◽

Raffaele Altara ◽

Ganesh V. Halade ◽

...

Keyword(s):

Myocardial Infarction ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M2 Macrophage Polarization

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Abstract 223: Histone Deacetylase Inhibition Mediated Macrophage Polarization Suppresses Matrix Metalloproteinase-9 Upregulation Post Myocardial Infarction

Circulation Research ◽

10.1161/res.113.suppl_1.a223 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Denise M Kimbrough ◽

Santhosh K Mani ◽

Chistine B Kern ◽

Harinath Kasiganesan ◽

Donald R Menick

Keyword(s):

Myocardial Infarction ◽

Matrix Metalloproteinase ◽

Macrophage Polarization ◽

Matrix Metalloproteinase 9 ◽

Class I ◽

M2 Macrophage ◽

Hdac Inhibition ◽

Ecm Remodeling ◽

M2 Macrophage Polarization ◽

Metalloproteinase 9

Background: Following a myocardial infarction (MI) the extracellular matrix (ECM) undergoes massive remodeling to prevent rupture and maintain cardiac output. Large increases in matrix metalloproteinase-9 (MMP-9) are associated with adverse ECM remodeling. We found that treatment with an HDAC inhibitor repressed post-MI upregulation of MMP-9. Significant sources of MMP-9 in the post-MI LV are M1 macrophages. Both phenotypes (M1 and M2) can contribute to MMP expression, but this is dependant on the phase of ECM remodeling. We hypothesize that HDAC inhibition regulates the post-MI expression of MMP-9 by mediating the M1 to M2 macrophage polarization. Methods: CD1 and MMP-9 β-gal reporter mice were induced with MI by LAD ligation then administered HDAC inhibitors: trichostatin A (TSA; class I and IIb), PD106 (class I), or Tubastatin A (HDAC 6) until termination at 5 or 7 days post-MI. Heart function evaluated by echocardiogram and cells or tissue by immunohistochemistry and immunoblotting. Results: The post-MI change in LV end-diastolic volume (49±9%) is significantly lower and ejection fraction (-44±8%) is improved with treatment of TSA vs. control (69±12%; -59±6%) respectively [n=28]. Immunohistochemical analysis revealed that infiltrating macrophages express MMP-9 at 5 and 7 days post-MI. HDAC inhibition decreases this expression and did so without reducing presence of macrophages within infarct. Immunoblotting shows that expression of all class I HDACs are increased following MI; however, in cultured macrophages only HDAC2 and HDAC3 are increased. TSA and PD106, inhibit control levels and lipopolysacharide (LPS) stimulated upregulation of MMP-9 in cultured RAW264.7 and bone marrow derived macrophages. Immunofluorescence revealed that treatment with PD106, Tub A, and TSA leads to M1 to M2 morphology specific polarization and maintenance of anti-inflammatory, M2, phenotype even with LPS stimulation in culture. However, only PD106 and TSA reduced MMP-9 expression in cultured macrophages. Conclusions: Macrophage mediated secretion of MMP-9 contributes to adverse ECM remodeling and loss of LV function post-MI. Class I HDAC inhibition promotes both M2 macrophage polarization and attenuates adverse remodeling by reducing MMP-9 expression.

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Human umbilical cord mesenchymal stem cells derived Exosomes attenuate injury of myocardial infarction by miR-24-3p-promoted M2 macrophage polarization

10.21203/rs.3.rs-406792/v1 ◽

2021 ◽

Author(s):

Feng Zhu ◽

Yihuan Chen ◽

Jingjing Li ◽

Ziying Yang ◽

Yang Lin ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Pathway Activation ◽

M2 Macrophage Polarization

Abstract Background- Exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs-Exo) were recommended as ideal substitutes for cell-free cardiac regenerative medicine, which had presented encouraging effects in regulating inflammation and attenuating myocardial injury. The phenotype of macrophages resident in myocardium were regulated dynamically in response to environmental cues, which may either protect against injury or promote maladaptive remodeling. However, the underlying mechanisms about UMSCs-Exo regulating macrophage polarization are still not well understood. Herein, we aimed to explore the effects of UMSCs-Exo on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI). Methods and Results- Exosomes were isolated from the supernatant of human umbilical cord mesenchymal stem cells (UMSCs) and transplanted by intramyocardial injection after MI. Our results showed that UMSCs-Exo improved cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. After depletion of macrophages with clodronate liposomes, the therapeutic effects of UMSCs-Exo were disrupted. Administrated with UMSC-Exo, macrophages are inclined to polarize towards M2 phenotype in inflammatory environment in vitro. The results of RNA-sequencing indicated Plcb3 was a key gene concerned in UMSCs-Exo facilitated M2 macrophage polarization. Further bioinformatics analysis revealed exosomal miR-24-3p as a potential effector mediated Plcb3 down regulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhanced M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in inflammatory environment. Furthermore, diminishing miR-24-3p expression in UMSCs-Exo attenuated the effects of UMSCs-Exo on M2 macrophage polarization. Conclusions- Our study demonstrated that macrophages, as important inflammatory regulators, participated in UMSCs-Exo mediated myocardial repair after MI. And the therapeutical effects were at least partially carried out by UMSCs-Exo promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanically, exosomal miR-24-3p inhibits the expression of Plcb3 and NF-κB pathway activation to promote M2 macrophage polarization.

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PHENOTYPIC HETEROGENEITY OF CARDIAC MACROPHAGES DURING WOUND HEALING FOLLOWING MYOCARDIAL INFARCTION: PERSPECTIVES IN CLINICAL RESEARCH

Siberian Medical Journal ◽

10.29001/2073-8552-2018-33-2-70-76 ◽

2018 ◽

Vol 33 (2) ◽

pp. 70-76 ◽

Cited By ~ 1

Author(s):

A. E. Gombozhapova ◽

Yu. V. Rogovskaya ◽

M. S. Rebenkova ◽

J. G. Kzhyshkowska ◽

V. V. Ryabov

Keyword(s):

Myocardial Infarction ◽

Wound Healing ◽

Cardiac Remodeling ◽

Phenotypic Heterogeneity ◽

Macrophage Infiltration ◽

Myocardial Regeneration ◽

Control Group ◽

M2 Macrophage ◽

Inflammatory Phase ◽

Regenerative Phase

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.

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