scholarly journals Interplay between Extracellular Matrix and Neutrophils in Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yanyan Zhu ◽  
Yumeng Huang ◽  
Qian Ji ◽  
Shengqiao Fu ◽  
Jia Gu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Inflammatory Microenvironment ◽  
Cell Matrix ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Almost All

The extracellular matrix (ECM) is a highly dynamic and complex network structure, which exists in almost all tissues and is the microenvironment that cells rely on for survival. ECM interacts with cells to regulate diverse functions, including differentiation, proliferation, and migration. Neutrophils are the most abundant immune cells in circulation and play key roles in orchestrating a complex series of events during inflammation. Neutrophils can also mediate ECM remodeling by providing specific matrix-remodeling enzymes (such as neutrophil elastase and metalloproteinases), generating neutrophil extracellular traps, and releasing exosomes. In turn, ECM can remodel the inflammatory microenvironment by regulating the function of neutrophils, which drives disease progression. Both the presence of ECM and the interplay between neutrophils and their extracellular matrices are considered an important and outstanding mechanistic aspect of inflammation. In this review, the importance of ECM will be considered, together with the discussion of recent advances in understanding the underlying mechanisms of the intricate interplay between ECM and neutrophils. A better comprehension of immune cell-matrix reciprocal dependence has exciting implications for the development of new therapeutic options for neutrophil-associated infectious and inflammatory diseases.

Abstract 122: Pharmacological Inhibition Of Macrophage Infiltration Prevents Myxomatous Valve Degeneration In Marfan Syndrome

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Na Xu ◽  
Katherine E Yutzey
Keyword(s):  
Immune Response ◽  
Extracellular Matrix ◽  
Marfan Syndrome ◽  
Macrophage Infiltration ◽  
Histological Evaluation ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Mitral Valves ◽  
Fibrillin 1 ◽  
Underlying Mechanisms

Introduction: Myxomatous valve degeneration (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. Currently, there is no medical therapy for the treatment of MVD. MVD in a mouse model of Marfan syndrome (MFS) is characterized leaflet thickening and increased macrophage infiltration, which are reduced with loss of C-C chemokine receptor type 2 (CCR2). However, the specific contributions of macrophages to pathological extracellular matrix (ECM) remodeling and underlying mechanisms are unknown. Hypothesis: Inhibition of macrophage infiltration by a CCR2 inhibitor blocks ECM abnormalities and MVD progression in mitral valves of MFS mice by suppressing the response to cytokine/chemokines. Methods: Mice with the mutation of Fibrillin 1 (Fbn1 C1039G/+ ) recapitulate histopathological features of MFS. Here, we tested the efficacy of a selective CCR2 antagonist RS504393 in the valves of MFS mice in the initiation (1-month-old) and the progression (2-month-old) of MVD, respectively. MFS mice were intraperitoneally injected with RS504393 at 2 mg/kg/d for 30 days. Histological evaluation and immunofluorescence for macrophages and ECM were performed. RNAseq was performed in mitral valves from 2-month old Fbn1 C1039G/+ mice with CCR2 knockout (CCR2 RFP/RFP ). Results: MFS valves revealed ECM abnormalities characterized by collagen fragmentation and proteoglycan accumulation. RS504393 treatment reduced infiltrating macrophages (MHCII+, CCR2+) in myxomatous valves. Remarkably, RS504393 was protective against both the initiation and the progression of MVD, detected by decreased mitral valve thickness and prevention of pathological ECM remodeling in MFS mice. RNAseq data confirmed increased leukocyte activation involved in immune response and abnormal extracellular matrix remodeling in MFS valves. CCR2 deficiency blocked macrophage infiltration and inhibited the response to cytokines in Fbn1 C1039G/+ valves. Conclusions: Our results show that macrophage infiltration is critical for progressive MVD. Moreover, CCR2 inhibition ameliorates MVD progression by preventing immune response. Thus, the CCR2 inhibitor RS504393 is a potential pharmacological candidate to treat MVD in MFS.

Consequences of Extracellular Matrix Remodeling in Headway and Metastasis of Cancer along with Novel Immunotherapies: A Great Promise for Future Endeavor

2021 ◽  
Vol 21 ◽  
Author(s):  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Extracellular Matrix ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Control Cell ◽  
Tumor Stroma ◽  
Great Promise ◽  
Matrix Remodeling ◽  
Extrinsic Factors ◽  
Ecm Remodeling ◽  
Normal Tissues

: Tissues are progressively molded by bidirectional correspondence between denizen cells and extracellular matrix (ECM) via cell-matrix connections along with ECM remodeling. The composition and association of ECM are spatiotemporally directed to control cell conduct and differentiation; however, dysregulation of ECM dynamics prompts the development of diseases, for example, cancer. Emerging information demonstrates that hypoxia may have decisive roles in metastasis. In addition, the sprawling nature of neoplastic cells and chaotic angiogenesis are increasingly influencing microcirculation as well as altering the concentration of oxygen. In various regions of the tumor microenvironment, hypoxia, an essential player in the multistep phase of cancer metastasis, is necessary. Hypoxia can be turned into an advantage for selective cancer therapy because it is much more severe in tumors than in normal tissues. Cellular matrix gives signaling cues that control cell behavior and organize cells' elements in tissue development and homeostasis. The interplay between intrinsic factors of cancer cells themselves, including their genotype and signaling networks, and extrinsic factors of tumor stroma, for example, ECM and ECM remodeling, together decide the destiny and behavior of tumor cells. Tumor matrix encourages the development, endurance, and invasion of neoplastic and immune cell activities to drive metastasis and debilitate treatment. Incipient evidence recommends essential parts of tumor ECM segments and their remodeling in controlling each progression of the cancer-immunity cycle. Scientists have discovered that tumor matrix dynamics as well as matrix remodeling in perspective to anti-tumor immune reactions are especially important for matrix-based biomarkers recognition and followed by immunotherapy and targeting specific drugs.

scholarly journals SPARC coordinates extracellular matrix remodeling and efficient recruitment to and migration of antigen-specific T cells in the brain following infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathryn E. McGovern ◽  
J. Philip Nance ◽  
Clément N. David ◽  
Reed E. S. Harrison ◽  
Shahani Noor ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Parasite Burden ◽  
Tissue Remodeling ◽  
Matrix Remodeling ◽  
Cell Trafficking ◽  
And Migration ◽  
The Brain

AbstractCentral nervous system (CNS) injury and infection can result in profound tissue remodeling in the brain, the mechanism and purpose of which is poorly understood. Infection with the protozoan parasite Toxoplasma gondii causes chronic infection and inflammation in the brain parenchyma. Control of parasite replication requires the continuous presence of IFNγ-producing T cells to keep T. gondii in its slowly replicating cyst form. During infection, a network of extracellular matrix fibers, revealed using multiphoton microscopy, forms in the brain. The origin and composition of these structures are unknown but the fibers have been observed to act as a substrate for migrating T cells. In this study, we show a critical regulator of extracellular matrix (ECM) remodeling, Secreted Protein, Acidic, Rich in Cysteine (SPARC), is upregulated in the brain during the early phases of infection in the frontal cortex. In the absence of SPARC, a reduced and disordered fibrous network, increased parasite burden, and reduced antigen-specific T cell entry into the brain points to a role for SPARC in T cell recruitment to and migration within the brain. We also report SPARC can directly bind to CCR7 ligands CCL19 and CCL21 but not CXCL10, and enhance migration toward a chemokine gradient. Measurement of T cell behavior points to tissue remodeling being important for access of immune cells to the brain and facilitating cellular locomotion. Together, these data identify SPARC as an important regulatory component of immune cell trafficking and access to the inflamed CNS.

scholarly journals Engineering cardiac microphysiological systems to model pathological extracellular matrix remodeling

2018 ◽  
Vol 315 (4) ◽  
pp. H771-H789 ◽  
Author(s):  
Nethika R. Ariyasinghe ◽  
Davi M. Lyra-Leite ◽  
Megan L. McCain
Keyword(s):  
Cardiovascular Disease ◽  
Extracellular Matrix ◽  
Myocardial Function ◽  
Myocardial Cell ◽  
Three Dimensions ◽  
Model Systems ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Microphysiological Systems

Many cardiovascular diseases are associated with pathological remodeling of the extracellular matrix (ECM) in the myocardium. ECM remodeling is a complex, multifactorial process that often contributes to declines in myocardial function and progression toward heart failure. However, the direct effects of the many forms of ECM remodeling on myocardial cell and tissue function remain elusive, in part because conventional model systems used to investigate these relationships lack robust experimental control over the ECM. To address these shortcomings, microphysiological systems are now being developed and implemented to establish direct relationships between distinct features in the ECM and myocardial function with unprecedented control and resolution in vitro. In this review, we will first highlight the most prominent characteristics of ECM remodeling in cardiovascular disease and describe how these features can be mimicked with synthetic and natural biomaterials that offer independent control over multiple ECM-related parameters, such as rigidity and composition. We will then detail innovative microfabrication techniques that enable precise regulation of cellular architecture in two and three dimensions. We will also describe new approaches for quantifying multiple aspects of myocardial function in vitro, such as contractility, action potential propagation, and metabolism. Together, these collective technologies implemented as cardiac microphysiological systems will continue to uncover important relationships between pathological ECM remodeling and myocardial cell and tissue function, leading to new fundamental insights into cardiovascular disease, improved human disease models, and novel therapeutic approaches.

scholarly journals Bone Mesenchymal Stem Cells Promote Extracellular Matrix Remodeling of Degenerated Nucleus Pulposus Cells via the miR-101-3p/EIF4G2 Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zeng Wang ◽  
Xiaolin Ding ◽  
Feifei Cao ◽  
Xishan Zhang ◽  
Jingguo Wu
Keyword(s):  
Extracellular Matrix ◽  
Nucleus Pulposus ◽  
Quantitative Polymerase Chain Reaction ◽  
Matrix Remodeling ◽  
Nucleus Pulposus Cells ◽  
Promoting Effect ◽  
Bone Mesenchymal Stem Cells ◽  
Ecm Remodeling ◽  
Lumbar Vertebral Fracture ◽  
Related Proteins

The etiology of lumbocrural pain is tightly concerned with intervertebral disk degeneration (IDD). Bone mesenchymal stem cell (BMSC)-based therapy bears potentials for IDD treatment. The properties of microRNA (miRNA)-modified BMSCs may be altered. This study investigated the role and mechanism of BMSCs promoting extracellular matrix (ECM) remodeling of degenerated nucleus pulposus cells (NPCs) via the miR-101-3p/EIF4G2 axis. NPCs were collected from patients with IDD and lumbar vertebral fracture (LVF). The expressions of miR-101-3p and ECM-related proteins, Collagen-I (Col-I) and Collagen-II (Col-II), were detected using the reverse transcription-quantitative polymerase chain reaction. The expressions of Col-I and Col-II, major non-collagenous component Aggrecan, and major catabolic factor Matrix metalloproteinase-13 (MMP-13) were detected using Western blotting. BMSCs were cocultured with degenerated NPCs from patients with IDD. Viability and apoptosis of NPCs were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. After the degenerated NPCs were transfected with the miR-101-3p inhibitor, the expressions of ECM-related proteins, cell viability, and apoptosis were detected. The targeting relationship between miR-101-3p and EIF4G2 was verified. Functional rescue experiments verified the effects of miR-101-3p and EIF4G2 on ECM remodeling of NPCs. Compared with the NPCs of patients with LVF, the degenerated NPCs of patients with IDD showed downregulated miR-101-3p, Col-II, and Aggrecan expressions and upregulated MMP-13 and Col-I expressions. BMSCs increased the expressions of miR-101-3p, Aggrecan, and Col-II, and decreased the expressions of MMP-13 and Col-I in degenerated NPCs. BMSCs enhanced NPC viability and repressed apoptosis. Downregulation of miR-101-3p suppressed the promoting effect of BMSCs on ECM remodeling. miR-101-3p targeted EIF4G2. Downregulation of EIF4G2 reversed the inhibiting effect of the miR-101-3p inhibitor on ECM remodeling. In conclusion, BMSCs increased the miR-101-3p expression in degenerated NPCs to target EIF4G2, thus promoting the ECM remodeling of NPCs.

scholarly journals Molecular profiling demonstrates modulation of immune cell function and matrix remodeling during luteal rescue†

2019 ◽  
Vol 100 (6) ◽  
pp. 1581-1596 ◽  
Author(s):  
Camilla K Hughes ◽  
Samar W Maalouf ◽  
Wan-Sheng Liu ◽  
Joy L Pate
Keyword(s):  
Extracellular Matrix ◽  
Corpus Luteum ◽  
Cell Function ◽  
Immune Cell ◽  
Cell Receptor ◽  
Cytokine Signaling ◽  
Matrix Remodeling ◽  
Proteomic Profiling ◽  
Interferon Tau ◽  
In Pregnancy

Abstract The corpus luteum (CL) is essential for maintenance of pregnancy in all mammals and luteal rescue, which occurs around day 16–19 in the cow, is necessary to maintain luteal progesterone production. Transcriptomic and proteomic profiling were performed to compare the day 17 bovine CL of the estrous cycle and pregnancy. Among mRNA and proteins measured, 140 differentially abundant mRNA and 24 differentially abundant proteins were identified. Pathway analysis was performed using four programs. Modulated pathways included T cell receptor signaling, vascular stability, cytokine signaling, and extracellular matrix remodeling. Two mRNA that were less in pregnancy were regulated by prostaglandin F2A in culture, while two mRNA that were greater in pregnancy were regulated by interferon tau. To identify mRNA that could be critical regulators of luteal fate, the mRNA that were differentially abundant during early pregnancy were compared to mRNA that were differentially abundant during luteal regression. Eight mRNA were common to both datasets, including mRNA related to regulation of steroidogenesis and gene transcription. A subset of differentially abundant mRNA and proteins, including those associated with extracellular matrix functions, were predicted targets of differentially abundant microRNA (miRNA). Integration of miRNA and protein data, using miRPath, revealed pathways such as extracellular matrix–receptor interactions, abundance of glutathione, and cellular metabolism and energy balance. Overall, this study has provided a comprehensive profile of molecular changes in the corpus luteum during maternal recognition of pregnancy and has indicated that some of these functions may be miRNA-regulated.

scholarly journals Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Cheri L. Lamb ◽  
Giovan N. Cholico ◽  
Daniel E. Perkins ◽  
Michael T. Fewkes ◽  
Julia Thom Oxford ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Matrix Remodeling ◽  
Mrna Levels ◽  
Gelatinase Activity ◽  
Ecm Remodeling ◽  
Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.

scholarly journals Myh10 deficiency leads to defective extracellular matrix remodeling and pulmonary disease

2018 ◽  
Author(s):  
Hyun-Taek Kim ◽  
Wenguang Yin ◽  
Young-June Jin ◽  
Paolo Panza ◽  
Felix Gunawan ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Alveolar Epithelium ◽  
Mouse Lung ◽  
Chain Gene ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Muscle Myosin ◽  
Alveolar Formation ◽  
Deposition Defects

AbstractImpaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

scholarly journals Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R

2020 ◽  
Author(s):  
Tal M. Dankovich ◽  
Rahul Kaushik ◽  
Gabriel Cassinelli Petersen ◽  
Philipp Emanuel Giro ◽  
Hannah Abdul Hadi ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Protein Synthesis ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Ecm Remodeling ◽  
Activity Dependent ◽  
The Brain ◽  
Brain Extracellular Matrix

SummaryThe brain extracellular matrix (ECM) assembles around neurons and synapses, and is thought to change only rarely, through proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. We found that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within ∼3 days, in an activity-dependent fashion.

scholarly journals Concepts of extracellular matrix remodelling in tumour progression and metastasis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Juliane Winkler ◽  
Abisola Abisoye-Ogunniyan ◽  
Kevin J. Metcalf ◽  
Zena Werb
Keyword(s):  
Extracellular Matrix ◽  
Tumour Progression ◽  
Metastatic Progression ◽  
Cell Matrix ◽  
Bidirectional Communication ◽  
Growth Increase ◽  
Matrix Interactions ◽  
Extracellular Matrix Remodelling ◽  
Underlying Mechanisms ◽  
Cell Matrix Interactions

Abstract Tissues are dynamically shaped by bidirectional communication between resident cells and the extracellular matrix (ECM) through cell-matrix interactions and ECM remodelling. Tumours leverage ECM remodelling to create a microenvironment that promotes tumourigenesis and metastasis. In this review, we focus on how tumour and tumour-associated stromal cells deposit, biochemically and biophysically modify, and degrade tumour-associated ECM. These tumour-driven changes support tumour growth, increase migration of tumour cells, and remodel the ECM in distant organs to allow for metastatic progression. A better understanding of the underlying mechanisms of tumourigenic ECM remodelling is crucial for developing therapeutic treatments for patients.

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