scholarly journals TGF-β-Induced CCR8 Promoted Macrophage Transdifferentiation into Myofibroblast-Like Cells

2021 ◽  
Author(s):  
Haijun Liu ◽  
Qingzhou Guan ◽  
Peng Zhao ◽  
Jiansheng Li
Keyword(s):  
Cell Migration ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Activation ◽  
The Body ◽  
Dependent Manner ◽  
Whole Process ◽  
Autophagy Inhibitor ◽  
Underlying Mechanisms ◽  
And Migration

Abstract Background: Idiopathic pulmonary fibrosis (IPF) is an unknown interstitial disease characterized by tissue fibrosis for which there currently is no effective treatment. Macrophages, as the main immune cells in lung tissue, are involved in the whole process of pulmonary fibrosis. In recent years, intercellular transformation has been widespread concerned in pulmonary fibrosis researchers. The macrophages which have flexible heterogeneity and plasticity participate in different physiological processes of the body. Cell chemokine receptor 8 (CCR8) expressed in a variety of cells plays a significant chemotactic role in inducing cell activation and migration. And it could also promote the differentiation of macrophages under certain environmental conditions. The current study is intended to explore the role of CCR8 in macrophage transdifferentiation into myofibroblast cells in idiopathic pulmonary fibrosis.Methods: We conducted experiments using Ccr8-specific small interfering RNA (siRNA), autophagy inhibitor (3-methyladenine,3-MA) and agonist (rapamycin) to explore the underlying mechanisms of macrophage transdifferentiation into myofibroblast cells in TGF-β induced pulmonary fibrosis. Results: The results indicated that TGF-β treatment increased the CCR8 protein level in a time- and a dose-dependent manner in MH-S, as well as macrophage transdifferentiation-related markers, including Vimentin, Collagen 1, and a-SMA, and cell migration. In addition, levels of autophagy were enhanced in macrophages treated with TGF-β. We found that 3-MA, an autophagy inhibitor decreased the expression levels of macrophage transdifferentiation-related markers and attenuated the cell migration. Furthermore, inhibition of CCR8 through using Ccr8-specific siRNA reduced the levels of autophagy and macrophage transdifferentiation-related markers, and inhibited the cell migration. Enhancing autophagy with rapamycin attenuated the inhibition effect of Ccr8-specific siRNA on macrophage migration and the increase of myofibroblast marker proteins.Conclusions: Our findings showed that the macrophages exposed to TGF-β had the potential to transdifferentiate into myofibroblasts and CCR8 was involved in the process. The effect of CCR8 in TGF-β-induced macrophage transdifferentiation occurs mainly through autophagy. Targeting the CCR8 may become a novel therapeutic strategy for the treatment of IPF.

scholarly journals Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

2018 ◽  
Vol 52 (5) ◽  
pp. 1800564 ◽  
Author(s):  
Grazyna Kwapiszewska ◽  
Anna Gungl ◽  
Jochen Wilhelm ◽  
Leigh M. Marsh ◽  
Helene Thekkekara Puthenparampil ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transcriptome Profiling ◽  
Lung Fibroblasts ◽  
Dependent Manner ◽  
Inflammatory Reactions ◽  
Beneficial Effects ◽  
Oncogene Homologue ◽  
And Migration

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node “extracellular matrix”. We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects via its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.

Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Benjamin J. Moss ◽  
Stefan W. Ryter ◽  
Ivan O. Rosas
Keyword(s):  
Epithelial Cell ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Activation ◽  
Alveolar Epithelial Cell ◽  
Cell Types ◽  
Annual Review ◽  
Publication Date ◽  
Metabolic Dysfunction ◽  
Epithelial Repair

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair. The dysregulated epithelial cell interacts with mesenchymal, immune, and endothelial cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation. Recent single-cell RNA sequencing studies of IPF lungs support the epithelial injury model. These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype. Here, we review the pathogenesis of IPF in the context of novel bioinformatics tools as strategies to discover pathways of disease, cell-specific mechanisms, and cell-cell interactions that propagate the profibrotic niche. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Overlapping effects of miR-21 inhibition and drugs for idiopathic pulmonary fibrosis in the post-myocardial infarction setting

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A Aimo ◽  
O Iborra Egea ◽  
C Passino ◽  
M Emdin
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Protein Interactions ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Biological Significance ◽  
Oral Drugs ◽  
Network Analyses ◽  
Funding Sources ◽  
And Migration

Abstract Background Intracoronary infusion of a specific miR-21 inhibitor after reperfused MI has been reported to reduce cardiac fibrosis and hypertrophy and improve cardiac function in pigs. Possible drawbacks of anti-miR-21 therapy are the high costs of this therapy, and the need for intracoronary administration, preferably some days after reperfusion. Oral drugs with anti-fibrotic actions could have similar effects than anti-miR-21, while overcoming the limitations of anti-miR-21. We tested this hypothesis by examining the two oral drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone). Methods We identified the regulatory profile of miR-21, which included 588 target genes. Only 99 of these interactions were supported by information from reporter gene assays. The biological significance of these 99 targets was evaluated through over-representation analysis, and 13 genes were identified as potentially related to cardiovascular diseases. We retrieved all known targets and main downstream interactions of nintedanib and pirfenidone from Drugbank. Finally, we cross-validated these datasets by using neural network analyses to search for protein-protein interactions, focusing on those shared by miR-21 inhibition, nintedanib and pirfenidone. Results Nintedanib and anti-miR21 had many targets in common, which could indicate an overlap in their corresponding mechanisms of action. The proto-oncogene SRC, which participates in gene transcription, immune response, apoptosis and migration, emerged as the leading signaling effector. By blocking SRC expression and many downstream effectors of SRC, as well as platelet-derived growth factor, nintedanib could decreased miR-21 expression. The molecular effects of nintedanib include inhibition of inflammation, fibrosis and angiogenesis, and then ultimately a relief from I/R injury, in a similar fashion than anti-miR-21. Contrary to nintedanib, no overlap between the effects of pirfenidone and anti-miR-21 was found. Conclusion Because of the remarkably strong overlapping with the targets of miR-21, there is a stronger rationale to assess nintedanib than pirfenidone as a cardioprotective therapy. If confirmed by experimental evidence, nintedanib could enter the stage of clinical trials to assess its efficacy in human patients with STEMI. Funding Acknowledgement Type of funding sources: None.

scholarly journals Signaling of Macrophage Inflammatory Protein (MIP)-3β Facilitates Dengue Virus-Induced Microglial Cell Migration

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 690
Author(s):  
Ming-Kai Jhan ◽  
Ting-Jing Shen ◽  
Po-Chun Tseng ◽  
Yung-Ting Wang ◽  
Chiou-Feng Lin
Keyword(s):  
Cell Migration ◽  
Dengue Virus ◽  
Viral Entry ◽  
Cell Activation ◽  
Microglial Cell ◽  
Inflammatory Protein ◽  
Infected Cells ◽  
Chemotactic Factors ◽  
And Migration ◽  
Macrophage Inflammatory Protein

The infection by dengue virus (DENV) of microglia causes cell activation and migration via a mechanism involving viral entry, RNA release, and Toll-like receptor 3 signaling. In this study, we demonstrated that secreted chemotactic factors present in microglial conditioned medium (MCM) facilitated cell motility in the murine BV2 microglial cells. The pharmacological disruption of lipid rafts/caveolae reduced DENV- and ultraviolet (UV)-inactivated MCM-induced microglial cell migration. An antibody-based cytokine/chemokine array showed an increase in macrophage inflammatory protein (MIP)-3β in MCM produced using DENV-infected cells. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) retarded UV-MCM-induced microglial cell migration. These results demonstrate that secreted MIP-3β and its effect on the JNK signaling pathways mediates DENV-induced BV2 microglial cell migration.

scholarly journals Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

2020 ◽  
Vol 21 (2) ◽  
pp. 524 ◽  
Author(s):  
Marina R. Hadjicharalambous ◽  
Mark A. Lindsay
Keyword(s):  
Chronic Disease ◽  
Epithelial Cell ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Activation ◽  
Lung Fibroblast ◽  
Biological Processes ◽  
Aberrant Expression ◽  
Non Coding Rnas

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by excessing scarring of the lungs leading to irreversible decline in lung function. The aetiology and pathogenesis of the disease are still unclear, although lung fibroblast and epithelial cell activation, as well as the secretion of fibrotic and inflammatory mediators, have been strongly associated with the development and progression of IPF. Significantly, long non-coding RNAs (lncRNAs) are emerging as modulators of multiple biological processes, although their function and mechanism of action in IPF is poorly understood. LncRNAs have been shown to be important regulators of several diseases and their aberrant expression has been linked to the pathophysiology of fibrosis including IPF. This review will provide an overview of this emerging role of lncRNAs in the development of IPF.

scholarly journals Metformin Suppressed CXCL8 Expression and Cell Migration in HEK293/TLR4 Cell Line

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhihui Xiao ◽  
Wenjun Wu ◽  
Vladimir Poltoratsky
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Tumor Cell ◽  
Nuclear Translocation ◽  
High Dose ◽  
Dependent Manner ◽  
Tumor Cell Proliferation ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Chronic inflammation is associated with cancer. CXCL8 promotes tumor microenvironment construction through recruiting leukocytes and endothelial progenitor cells that are involved in angiogenesis. It also enhances tumor cell proliferation and migration. Metformin, type II diabetes medication, demonstrates anticancer properties via suppressing inflammation, tumor cell proliferation, angiogenesis, and metastasis. This study intended to address the role of metformin in regulation of CXCL8 expression and cell proliferation and migration. Our data indicated that metformin suppressed LPS-induced CXCL8 expression in a dose-dependent manner through inhibiting NF-κB, but not AP-1 and C/EBP, activities under the conditions we used. This inhibitory effect of metformin is achieved through dampening LPS-induced NF-κB nuclear translocation. Cell migration was inhibited by metformin under high dose (10 mM), but not cell proliferation.

Pleural Mesothelial Cell Activation in Idiopathic Pulmonary Fibrosis

CHEST Journal ◽  
2012 ◽  
Vol 142 (4) ◽  
pp. 953A
Author(s):  
Jason Zolak ◽  
Rajesh Jagirdar ◽  
Ranu Surolia ◽  
Octavio Oliva ◽  
Suman Karki ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Activation ◽  
Mesothelial Cell

scholarly journals PACAP and VIP Modulate LPS-induced Microglial Activation and Trigger Distinct Phenotypic Changes in Murine BV2 Microglial Cells

2021 ◽  
Author(s):  
Jocelyn Karunia ◽  
Aram Niaz ◽  
Mawj Mandwie ◽  
Sarah Thomas Broome ◽  
Kevin A Keay ◽  
...  
Keyword(s):  
Cell Migration ◽  
Microglial Activation ◽  
Activation Markers ◽  
Bv2 Cells ◽  
Bv2 Microglia ◽  
Cell Subpopulations ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Phenotypic Shift ◽  
Bv2 Microglial Cells

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally-related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP or VIP differentially affected microglial activation, morphology and cell migration. We found that both peptides attenuated LPS-induced expression of the microglial activation markers Iba1 and iNOS (###p<0.001), as well as the pro-inflammatory mediators IL-1β, IL-6, Itgam and CD68 (###p<0.001). In contrast, treatment with PACAP or VIP exerted distinct effects on microglial morphology and migration. PACAP reversed LPS-induced soma enlargement and increased the percentage of small-sized, rounded cells (54.09% vs 12.05% in LPS-treated cells), whereas VIP promoted a phenotypic shift towards cell subpopulations with mid-sized, spindle-shaped soma (48.41% vs 31.36% in LPS-treated). Additionally, PACAP was more efficient than VIP in restoring LPS-induced impairment of cell migration and the expression of urokinase plasminogen activator (uPA) in BV2 cells compared with VIP. These results suggest that whilst both PACAP and VIP exert similar immunosuppressive effects in activated BV2 microglia, each peptide triggers distinctive shifts towards phenotypes of differing morphologies and with differing migration capacities.

scholarly journals Compound Phyllanthus urinaria L Inhibits HBV-Related HCC through HBx-SHH Pathway Axis Inactivation

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Yun Li ◽  
Mingjie Jiang ◽  
Mingshun Li ◽  
Yingjie Chen ◽  
Chunshan Wei ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Sonic Hedgehog ◽  
Dependent Manner ◽  
Shh Pathway ◽  
Phyllanthus Urinaria ◽  
Gli 1 ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Dose Dependent

Compound Phyllanthus urinaria L (CP) is a traditional formula widely used in clinical practice for hepatocellular carcinoma (HCC), especially HBV-related HCC. HBx, HBV X gene encoded X protein, has positive correlation with the abnormal SHH pathway in HBV-related HCC. So, we predicted that CP has the capability of anti-HBV-related HCC maybe via inactivating the HBx-Hedgehog pathway axis. HepG2-HBx cells, HBx overexpression, were treated with CP (70μg/ml and 35 μg/ml, respectively) for 48 hours and the mice which received the HepG2-HBx cells were treated with CP (625mg/kg and 300 mg/kg, respectively) for 17 days to evaluate the effect of CP on HBV-related HCC. HBx could accelerate HepG2 cells proliferation, clone formation, and migration in vitro and also could strengthen tumor growth in mice. However, CP could significantly decrease HepG2-HBx cells proliferation, clone formation, and migration in vitro and also could inhibit tumors growth in mice in a dose-dependent manner. Mechanism studies suggested that HBx upregulated the mRNA and proteins expression of Sonic hedgehog (SHH), transmembrane receptor patched (PTCH-1), smoothened (SMO), oncogene homolog transcription factors-1 (GLI-1), and oncogene homolog transcription factors-2 (GLI-2), which are compositions of the SHH pathway. CP could inhibit the mRNA and proteins expression of SHH, PTCH-1, GLI-1, and HBx. It may be one of the underlying mechanisms of CP to delay the HBV-related HCC development through the HBx-SHH pathway axis inactivation.

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