scholarly journals ECM1 is an essential factor for the determination of M1 macrophage polarization in IBD in response to LPS stimulation

2020 ◽  
Vol 117 (6) ◽  
pp. 3083-3092 ◽  
Author(s):  
Yaguang Zhang ◽  
Xuezhen Li ◽  
Zhongguang Luo ◽  
Liyan Ma ◽  
Songling Zhu ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Intestinal Inflammation ◽  
Macrophage Polarization ◽  
Extracellular Matrix Protein ◽  
Mechanistic Study ◽  
Macrophage Phenotype ◽  
Inflammatory Conditions ◽  
Arginase 1 ◽  
M1 Macrophage ◽  
Macrophage Colony

Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the ECM1 gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β

2018 ◽  
Vol 132 (11) ◽  
pp. 1199-1213 ◽  
Author(s):  
Cheng Zhang ◽  
Juan-Juan Qin ◽  
Fu-Han Gong ◽  
Jing-Jing Tong ◽  
Wen-Lin Cheng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Matrix Protein ◽  
Foam Cell ◽  
Cell Formation ◽  
Direct Interaction ◽  
Extracellular Matrix Protein ◽  
Mechanistic Study ◽  
Foam Cell Formation ◽  
Atheromatous Plaques ◽  
Inflammatory Processes

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE−/− mice after high-fat diet treatment. Mindin−/−ApoE−/− mice and macrophage-specific mindin overexpression in ApoE−/− mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin−/−ApoE−/− mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β.

scholarly journals Lipocalin 2 is a Regulator Of Macrophage Polarization and NF-κB/STAT3 Pathway Activation

2014 ◽  
Vol 28 (10) ◽  
pp. 1616-1628 ◽  
Author(s):  
Hong Guo ◽  
Daozhong Jin ◽  
Xiaoli Chen
Keyword(s):  
Time Course ◽  
Target Genes ◽  
Macrophage Polarization ◽  
Lipocalin 2 ◽  
Regulation Of Expression ◽  
Arginase 1 ◽  
Pathway Activation ◽  
M1 Macrophage ◽  
Stat3 Phosphorylation ◽  
Pre Treatment

Lipocalin 2 (Lcn2) has been previously characterized as an adipokine/cytokine and implicated in obesity and inflammation. Herein, we investigated the role and potential mechanism of Lcn2 in the regulation of macrophage polarization in obesity-associated inflammation. We observed that Lcn2−/− mice displayed an up-regulation of expression of M1 macrophage marker Cd11c but a down-regulation of M2 marker arginase 1 in adipose tissue and liver of mice upon a high-fat diet feeding. Lcn2-deficient bone marrow–derived macrophages (BMDMs) were more sensitive to lipopolysaccharide (LPS) stimulation, leading to a more profound up-regulation of expression of pro-inflammatory markers than wild-type (WT) BMDMs. Accordingly, LPS stimulation elicited an increase in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), c-Jun, and STAT3 signaling pathways as well as an up-regualtion of expression of NF-κB and STAT3 target genes such as IL-1β, IL-6, iNOS, and MCP-1 in Lcn2−/− BMDMs compared with WT controls. Pre-treatment of recombinant Lcn2 attenuated LPS-stimulated degradation of IκBα and STAT3 phosphorylation as well as LPS-induced gene expression of IL-6 and iNOS in Lcn2−/− BMDMs. Moreover, the NFκB inhibitor markedly blocked LPS-stimulated STAT3 phosphorylation in Lcn2−/− BMDMs. These results together with the time course of Lcn2 secretion, NFκB and STAT3 phosphorylation in response to LPS stimulation, suggest that Lcn2 plays a role as an anti-inflammatory regulator in macrophage activation via modulating a feed-forward activation of NFκB-STAT3 loop.

scholarly journals Hyperoxia Exacerbates Postnatal Inflammation-Induced Lung Injury in Neonatal BRP-39 Null Mutant Mice Promoting the M1 Macrophage Phenotype

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Mansoor A. Syed ◽  
Vineet Bhandari
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Continuous Exposure ◽  
Macrophage Phenotype ◽  
Cell Counts ◽  
M1 Macrophage ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Anti Inflammatory

Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages.Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury.Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. Forin vivostudies, wild-type (WT) and BRP-39−/−mice received continuous exposure to 21% O2(control mice) or 100% O2from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed.Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39−/−mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice.Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury.

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

Cells ◽  
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.

Abstract 19: Deletion of Myeloid GSK3α Attenuates Atherosclerosis and Promotes an M2 Macrophage Phenotype

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Cameron McAlpine ◽  
Aric Huang ◽  
Abby Emdin ◽  
Nicole Banko ◽  
Daniel Beriault ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Atherosclerotic Lesion ◽  
M2 Macrophage ◽  
Lesion Volume ◽  
Macrophage Phenotype ◽  
Expression Of Genes ◽  
M1 Macrophage ◽  
Deficient Mice

Objective: Glycogen synthase kinase (GSK)-3α/β has been implicated in the pathogenesis of diseases including diabetes, cancer, Alzheimer’s and atherosclerosis. The tissue and homolog specific functions of GSK3α and β in atherosclerosis are unknown. This study examines the effect of hepatocyte or myeloid cell specific deletion of GSK3α or GSK3β on atherosclerosis in LDLR-/- mice. Approach and results: We ablated GSK3α or GSK3β expression in hepatic or myeloid cells of LDLR-/- mice and mice were fed a high fat diet for 10 weeks. GSK3α or GSK3β deficiency in hepatic or myeloid cells did not affect metabolic parameters, including plasma lipid levels. Hepatic deletion of GSK3α or GSK3β did not affect the development of atherosclerosis or hepatic lipid content. Myeloid deletion of GSK3α, but not GSK3β, reduced atherosclerotic lesion volume as well as lesion complexity. Mice lacking GSK3α in myeloid cells had a less inflammatory and more anti-inflammatory plasma cytokine profile. Macrophages within atherosclerotic lesions of myeloid GSK3α deficient mice, but not GSK3β deficient mice, displayed reduced expression of markers associated with M1 macrophage polarization and enhanced expression of the M2 markers. Finally, bone marrow derived macrophages were isolated and differentiated into classical M1 macrophages or alternative M2 macrophages in vitro. GSK3α deletion, but not GSK3β deletion, attenuated the expression of genes associated with M1 polarization while promoting the expression of genes associated with M2 polarization. Mechanistically, GSK3α regulated macrophage polarization by modulating the phosphorylation and activation of STAT transcription factors. Conclusions: Our findings suggest that deletion of myeloid GSK3α attenuates the progression of atherosclerosis by regulating STAT activation and promoting an M2 macrophage phenotype.

scholarly journals Role of microRNA-21 and Its Underlying Mechanisms in Inflammatory Responses in Diabetic Wounds

2020 ◽  
Vol 21 (9) ◽  
pp. 3328 ◽  
Author(s):  
Cole Liechty ◽  
Junyi Hu ◽  
Liping Zhang ◽  
Kenneth W. Liechty ◽  
Junwang Xu
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Regulation Of Gene Expression ◽  
Mouse Skin ◽  
M2 Macrophage ◽  
Central Feature ◽  
Macrophage Phenotype ◽  
Macrophage Cells ◽  
M1 Macrophage ◽  
Diabetic Wounds

A central feature of diabetic wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of pro-inflammatory (M1) macrophages in diabetic wounds. Persistence of the M1 macrophage phenotype and failure to transition to the regenerative or pro-remodeling (M2) macrophage phenotype plays an indispensable role in diabetic wound impairment; however, the mechanism underlying this relationship remains unclear. Recently, microRNAs have been shown to provide an additional layer of regulation of gene expression. In particular, microRNA-21 (miR-21) is essential for an inflammatory immune response. We hypothesize that miR-21 plays a role in regulating inflammation by promoting M1 macrophage polarization and the production of reactive oxygen species (ROS). To test our hypothesis, we employed an in vivo mouse skin wound model in conjunction with an in vitro mouse model to assess miR-21 expression and macrophage polarization. First, we found that miR-21 exhibits a distinct expression pattern in each phase of healing in diabetic wounds. MiR-21 abundance was higher during early and late phases of wound repair in diabetic wounds, while it was significantly lower in the middle phase of wounding (at days 3 and 7 following wounding). In macrophage cells, M1 polarized macrophages exhibited an upregulation of miR-21, as well as the M1 and pro-inflammatory markers IL-1b, TNFa, iNos, IL-6, and IL-8. Overexpression of miR-21 in macrophage cells resulted in an upregulation of miR-21 and also increased expression of the M1 markers IL-1b, TNFa, iNos, and IL-6. Furthermore, hyperglycemia induced NOX2 expression and ROS production through the HG/miR-21/PI3K/NOX2/ROS signaling cascade. These findings provide evidence that miR-21 is involved in the regulation of inflammation. Dysregulation of miR-21 may explain the abnormal inflammation and persistent M1 macrophage polarization seen in diabetic wounds.

scholarly journals Astragaloside IV Alleviates the Experimental DSS-Induced Colitis by Remodeling Macrophage Polarization Through STAT Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Lianlian Tian ◽  
Jun-Long Zhao ◽  
Jian-Qin Kang ◽  
Shi-bo Guo ◽  
Nini Zhang ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Macrophage Polarization ◽  
Experimental Colitis ◽  
Clinical Activity ◽  
Macrophage Phenotype ◽  
Astragaloside Iv ◽  
Stat Signaling ◽  
Inflammatory Macrophages

Inflammatory bowel disease (IBD) is characterized by chronic and relapsing intestinal inflammation, which currently lacks safe and effective medicine. Some previous studies indicated that Astragaloside IV (AS-IV), a natural saponin extracted from the traditional Chinese medicine herb Ligusticum chuanxiong, alleviates the experimental colitis symptoms in vitro and in vivo. However, the mechanism of AS-IV on IBD remains unclear. Accumulating evidence suggests that M2-polarized intestinal macrophages play a pivotal role in IBD progression. Here, we found that AS-IV attenuated clinical activity of DSS-induced colitis that mimics human IBD and resulted in the phenotypic transition of macrophages from immature pro-inflammatory macrophages to mature pro-resolving macrophages. In vitro, the phenotype changes of macrophages were observed by qRT-PCR after bone marrow-derived macrophages (BMDMs) were induced to M1/M2 and incubated with AS-IV, respectively. In addition, AS-IV was effective in inhibiting pro-inflammatory macrophages and promoting the pro-resolving macrophages to ameliorate experimental colitis via the regulation of the STAT signaling pathway. Hence, we propose that AS-IV can ameliorate experimental colitis partially by modulating macrophage phenotype by remodeling the STAT signaling, which seems to have an essential function in the ability of AS-IV to alleviate the pathological progress of IBD.

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

2018 ◽  
Vol 115 (3) ◽  
pp. 614-624 ◽  
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.

scholarly journals Inhibition of PAI-1 attenuates perirenal fat inflammation and the associated nephropathy in high-fat diet-induced obese mice

2019 ◽  
Vol 316 (2) ◽  
pp. E260-E267 ◽  
Author(s):  
Yong Liu ◽  
Lin Wang ◽  
Mao Luo ◽  
Ni Chen ◽  
Xin Deng ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Diabetic Nephropathy ◽  
High Fat Diet ◽  
Matrix Protein ◽  
Macrophage Polarization ◽  
Extracellular Matrix Protein ◽  
Obese Mouse ◽  
High Fat ◽  
Pai 1 ◽  
Perirenal Fat

Plasminogen activator inhibitor-1 (PAI-1) is increasingly recognized as a mediator in extracellular matrix (ECM) accumulation in diabetic nephropathy. Previous studies have implicated PAI-1 in adipose tissue (AT) expansion, while also contributing to insulin resistance. As inflammation is also known to occur in perirenal AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model, PAI-1 contributes to macrophage-mediated inflammation and diabetic nephropathy. The HFD mice showed increased expression of PAI-1 in perirenal fat and also displayed increased fat weight and macrophage numbers. We found that the macrophage polarization, proinflammatory macrophage-M1-phenotype, including CD11c, IL-6, and monocyte chemoattractant protein-1, were increased by an HFD and decreased by either the genetic depletion of PAI-1 or treatment with the PAI-1 inhibitor, PAI-039. Similarly, an enhanced anti-inflammatory M2-phenotype, including CD206 and IL-10, was accompanied by either the genetic deletion of PAI-1 or PAI-039 treatment. Furthermore, the inhibition of PAI-1 reduced HFD-induced renal histological lesions and abated profibrotic/extracellular-matrix protein. Collectively, our findings provide support that PAI-1 contributes to the development of inflammation in perirenal fat and correlates with the development of diabetic nephropathy in HFD-induced obesity.

scholarly journals Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ying Zhang ◽  
Conghui Zhang ◽  
Lixi Li ◽  
Xinjun Liang ◽  
Peng Cheng ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Macrophage Polarization ◽  
Lymphatic Vessels ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
M1 Macrophage ◽  
Close Relationship ◽  
Stage Renal Disease

AbstractInflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

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