Cardiac fibroblasts regulate macrophage ontogeny, phenotype and function during cardiac injury
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PROVIDER: PRJNA487063 | ENA |
REPOSITORIES: ENA
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Project description:Two types of monocytes, inflammatory and patrolling, infiltrate the hearts in both human myocarditis and murine experimental autoimmune myocarditis (EAM) model. The fates and functions of these infiltrating monocytes governing the progression of heart failure remain unclear. Here, we created parabiotic EAM and naïve mice to show that cardiac inflammation facilitate monocyte-to-macrophage differentiation. Using a combination of flow cytometry, time lapsed imaging and transmission electron microscopy, we demonstrated in vitro that cardiac fibroblasts interact with monocytes and are instrumental in facilitating monocyte-to-macrophage differentiation. Moreover, IL-17A stimulated cardiac fibroblasts completely arrested Ly6Clo monocyte proliferation and inhibited both Ly6Chi and Ly6Clo monocyte-to-macrophage differentiation both in vitro and in vivo after intracardiac injections of monocytes into the hearts. Intriguingly, IL-17A signaling through cardiac fibroblasts also significantly downregulated Mer tyrosine kinase (MerTK) expressions on Ly6Chi monocyte-derived macrophages, thus jeopardizing their phagocytic abilities. Collectively, our results implicate divergent fates and functions of heart-infiltrating monocytes influenced by cardiac fibroblasts.
2021-08-01 | GSE118861 | GEO
Project description:"Youthful" Phenotype of c-Kit+ Cardiac Fibroblasts [DDR2_cKit]
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Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.
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Project description:YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction
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Project description:Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
2022-03-03 | GSE168742 | GEO
Project description:Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial pro-inflammatory response followed by an anti-inflammatory or reparative response post-MI is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and essential for cardiac repair as they can adopt both pro-inflammatory (M1) or anti-inflammatory/reparative (M2) phenotypes to modulate inflammatory and reparative response, respectively. YAP and TAZ are the key mediators of the Hippo signaling pathway and essential for cardiac regeneration and repair. However, their role in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing M1 or M2 polarization. Genetic deletion of YAP/TAZ leads to impaired M1 polarization and enhanced M2 polarization. Consistently, YAP activation/overexpression enhanced M1 and impaired M2 polarization. We show that YAP/TAZ promote M1 polarization by increasing IL6 expression, and impede M2 polarization by decreasing Arg1 expression through interaction with the HDAC3-NCoR1 repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, and hypertrophy and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro- and anti-inflammatory responses post-MI.
2020-10-02 | GSE158889 | GEO
Project description:Macrophage polarization followed by acute myocardial infarction (MI) is essential for the regulation of inflammation and scar formation. Tripartite motif-containing protein 21 (TRIM21), a member of E3 ubiquitin ligases, is a crucial mediator in the process of inflammation and heart failure. However, the potential roles of TRIM21 in modulating post-MI inflammation and macrophage polarization remain elusive. We detected that the levels of TRIM21 were significantly reduced in macrophages of WT mice after MI. In contrast, MI was ameliorated in TRIM21 knockout (TRIM21-/-) mice with improved cardiac remodeling, characterized by a marked decrease in mortality, increased wall thickness, and improved cardiac function in comparison with wild-type (WT) MI mice. Importantly, TRIM21 deficiency decreased the post-MI apoptosis and DNA damage in the hearts of mice, and the accumulation of M1 phenotype macrophages in infarcted hearts significantly decreased in TRIM21-/- mice compared with WT controls. Mechanistically, depletion of TRIM21 orchestrated the process of M1 macrophage polarization via a PI3K/Akt signaling pathway. Overall, these data reveal that TRIM21 drives the inflammatory response and cardiac remodeling after MI via stimulating M1 macrophage polarization through a PI3K/Akt signaling pathway.
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