A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization

Wen, Guangwu; Zhang, Cheng; Chen, Qishan; Luong, Le Anh; Mustafa, Arif; Ye, Shu; Xiao, Qingzhong

doi:10.1074/jbc.m114.634022

Cited by 41 publications

(45 citation statements)

References 40 publications

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“…For in vitro foam cell formation analyses, bone marrow mononuclear cells isolated from WT or NE_KO mice were differentiated into BMMs as described in our previous study, 23 followed by an incubation with 5 lg/mL of DiI-Ac-LDL (10574053, Fisher Scientific) for 5 hours. The cells were fixed with paraformaldehyde and counterstained with DAPI.…”

Section: Foam Cell Formation Assaymentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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BackgroundTo investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.Methods and Results NE genetic–deficient mice (Apolipoprotein E−/−/NE −/− mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high‐fat diet (HFD)–fed wild‐type (WT) (Apolipoprotein E−/−) mice but, as expected, not in NE‐deficient mice. Selective NE knockout markedly reduced HFD‐induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE‐deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE −/− bone marrow cells significantly reduced HFD‐induced atherosclerosis, while bone marrow reconstitution of NE −/− mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE‐deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP‐binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux.ConclusionsWe outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

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Section: Foam Cell Formation Assaymentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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“…Real-time quantitative PCR (RT-qPCR) was performed as described previously. 8,23,29,30,36 Briefly, total RNAs containing small RNAs (miRNAs) were extracted from cells using the mirVana Protein and RNA Isolation System Kit (Thermo Fisher Scientific Inc) or TRI reagent (Sigma-Aldrich), according to the manufacturer's instructions, and subjected to DNase I (Sigma-Aldrich) digestion to remove potential DNA contamination. Reverse transcription for long RNA was performed using an Improm-II RT kit (Promega) with RNase inhibitor (Promega) and Random primers (Promega).…”

Section: Reverse Transcriptase-quantitative Pcr For Mrna and Mirnasmentioning

confidence: 99%

NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia

Afzal

Luong

Chen

et al. 2016

JAHA

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BackgroundMicroRNA miR‐214 has been implicated in many biological cellular functions, but the impact of miR‐214 and its target genes on vascular smooth muscle cell (VSMC) proliferation, migration, and neointima smooth muscle cell hyperplasia is unknown.Methods and ResultsExpression of miR‐214 was closely regulated by different pathogenic stimuli in VSMCs through a transcriptional mechanism and decreased in response to vascular injury. Overexpression of miR‐214 in serum‐starved VSMCs significantly decreased VSMC proliferation and migration, whereas knockdown of miR‐214 dramatically increased VSMC proliferation and migration. Gene and protein biochemical assays, including proteomic analyses, showed that NCK associated protein 1 (NCKAP1)—a major component of the WAVE complex that regulates lamellipodia formation and cell motility—was negatively regulated by miR‐214 in VSMCs. Luciferase assays showed that miR‐214 substantially repressed wild‐type but not the miR‐214 binding site mutated version of NCKAP1 3′ untranslated region luciferase activity in VSMCs. This result confirmed that NCKAP1 is the functional target of miR‐214 in VSMCs. NCKAP1 knockdown in VSMCs recapitulates the inhibitory effects of miR‐214 overexpression on actin polymerization, cell migration, and proliferation. Data from cotransfection experiments also revealed that inhibition of NCKAP1 is required for miR‐214–mediated lamellipodia formation, cell motility, and growth. Importantly, locally enforced expression of miR‐214 in the injured vessels significantly reduced NCKAP1 expression levels, inhibited VSMC proliferation, and prevented neointima smooth muscle cell hyperplasia after injury.ConclusionsWe uncovered an important role of miR‐214 and its target gene NCKAP1 in modulating VSMC functions and neointima hyperplasia. Our findings suggest that miR‐214 represents a potential therapeutic target for vascular diseases.

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“…For example, MMP12 and MMP28, both macrophage products, either promote or restrict macrophage influx into lung (10, 11), and MMP8 promotes M2 polarization (12). In addition, we reported that MMP28 and TIMP3, an MMP inhibitor, moderate M1 activation of macrophages in models of lung infection and fibrosis (13, 14).…”

Section: Introductionmentioning

confidence: 99%

Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation

McMahan

Birkland

Smigiel

et al. 2016

The Journal of Immunology

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Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. Here, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow-derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wildtype mice survived infection with minimal morbidity, 50% of Mmp10−/− mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were about 3-fold greater in infected Mmp10−/− lungs than in wildtypes. Adoptive transfer of wildtype BMDM normalized infection-induced morbidity in Mmp10−/− recipients to wildtype levels demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, while M2 markers were reduced in Mmp10−/− tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10−/− BMDM long after they were down-regulated in wildtype cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the pro-inflammatory response of resident and infiltrating macrophages.

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A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization

Cited by 41 publications

References 40 publications

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

NCK Associated Protein 1 Modulated by miRNA‐214 Determines Vascular Smooth Muscle Cell Migration, Proliferation, and Neointima Hyperplasia

Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation

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