Diversity, Mechanisms, and Significance of Macrophage Plasticity

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2019, Volume and Issue: 15(1), P. 123 - 147

Published: Sept. 18, 2019

Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow-derived cells); the organ context; activation or deactivation various signals contexts microbial invasion, tissue damage, and metabolic derangement; polarization adaptive T cell responses. Classic responses macrophages include tolerance, priming, wide spectrum states, including M1, M2, M2-like. Moreover, can retain long-term imprinting encounters (trained innate immunity). Single-cell analysis mononuclear phagocytes health disease has added new dimension to our understanding macrophage differentiation activation. Epigenetic landscapes, transcription factors, microRNA networks underlie adaptability different environmental cues. Macrophage plasticity, an essential component chronic inflammation, its involvement human diseases, most notably cancer, discussed here as paradigm.

Language: Английский

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Cells of the adult human heart

Nature, Journal Year: 2020, Volume and Issue: 588(7838), P. 466 - 472

Published: Sept. 24, 2020

Abstract Cardiovascular disease is the leading cause of death worldwide. Advanced insights into mechanisms and therapeutic strategies require a deeper understanding molecular processes involved in healthy heart. Knowledge full repertoire cardiac cells their gene expression profiles fundamental first step this endeavour. Here, using state-of-the-art analyses large-scale single-cell single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight cellular heterogeneity cardiomyocytes, pericytes fibroblasts, reveal distinct atrial ventricular subsets with diverse developmental origins specialized properties. We define complexity vasculature its changes along arterio-venous axis. In immune compartment, identify cardiac-resident macrophages inflammatory protective transcriptional signatures. Furthermore, cell-to-cell interactions different networks macrophages, fibroblasts cardiomyocytes between atria ventricles that are from those skeletal muscle. human cell atlas improves our provides valuable reference for future studies.

Language: Английский

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Fibrosis: from mechanisms to medicines

Nature, Journal Year: 2020, Volume and Issue: 587(7835), P. 555 - 566

Published: Nov. 25, 2020

Language: Английский

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Cardiac fibrosis

Cardiovascular Research, Journal Year: 2020, Volume and Issue: 117(6), P. 1450 - 1488

Published: Oct. 26, 2020

Abstract Myocardial fibrosis, the expansion of cardiac interstitium through deposition extracellular matrix proteins, is a common pathophysiologic companion many different myocardial conditions. Fibrosis may reflect activation reparative or maladaptive processes. Activated fibroblasts and myofibroblasts are central cellular effectors in serving as main source proteins. Immune cells, vascular cells cardiomyocytes also acquire fibrogenic phenotype under conditions stress, activating fibroblast populations. Fibrogenic growth factors (such transforming factor-β platelet-derived factors), cytokines [including tumour necrosis factor-α, interleukin (IL)-1, IL-6, IL-10, IL-4], neurohumoral pathways trigger signalling cascades binding to surface receptors, downstream cascades. In addition, matricellular macromolecules deposited remodelling myocardium regulate assembly, while modulating signal transduction protease factor activity. Cardiac can sense mechanical stress mechanosensitive ion channels integrins, intracellular that contribute fibrosis response pressure overload. Although subpopulations fibroblast-like exert important protective actions both interstitial/perivascular ultimately fibrotic changes perturb systolic diastolic function, play an role pathogenesis arrhythmias. This review article discusses molecular mechanisms involved various diseases, including infarction, heart failure with reduced preserved ejection fraction, genetic cardiomyopathies, diabetic disease. Development fibrosis-targeting therapies for patients diseases will require not only understanding functional pluralism dissection basis remodelling, but appreciation heterogeneity fibrosis-associated

Language: Английский

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Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Nature Immunology, Journal Year: 2018, Volume and Issue: 20(1), P. 29 - 39

Published: Dec. 5, 2018

Language: Английский

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Cardioimmunology: the immune system in cardiac homeostasis and disease

Nature reviews. Immunology, Journal Year: 2018, Volume and Issue: 18(12), P. 733 - 744

Published: Sept. 18, 2018

Language: Английский

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Tissue Resident CCR2− and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury

Circulation Research, Journal Year: 2019, Volume and Issue: 124(2), P. 263 - 278

Published: Jan. 17, 2019

Recent advancements have brought to light the origins, complexity, and functions of tissue-resident macrophages. However, in context tissue injury or disease, large numbers monocytes infiltrate heart are thought contribute adverse remodeling failure pathogenesis. Little is understood about diversity monocyte-derived macrophages recruited after myocardial injury, including mechanisms that regulate monocyte recruitment fate specification.We sought test hypothesis distinct subsets CCR2- (C-C chemokine receptor 2) CCR2+ orchestrate specification injury.We reveal numerous mouse models cardiomyocyte cell death (permanent infarction, reperfused diphtheria toxin ablation), there a shift macrophage ontogeny whereby predominately replaced by infiltrating Using syngeneic cardiac transplantation model ischemia-reperfusion distinguish from populations combination with intravital 2-photon microscopy, we demonstrate differentially orchestrated Tissue-resident promote through an MYD88 (myeloid differentiation primary response 88)-dependent mechanism results release MCPs (monocyte chemoattractant proteins) mobilization. In contrast, inhibit recruitment. CD (cluster differentiation) 169-DTR (diphtheria receptor) CCR2-DTR mice, further show selective depletion either before infarction divergent effects on left ventricular function, remodeling, Finally, using single-cell RNA sequencing, instruct specification.Collectively, these observations establish mechanistic basis which initially injured provide new insights into heterogeneity

Language: Английский

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Reappraising the role of inflammation in heart failure

Nature Reviews Cardiology, Journal Year: 2020, Volume and Issue: 17(5), P. 269 - 285

Published: Jan. 22, 2020

Language: Английский

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Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury

eLife, Journal Year: 2019, Volume and Issue: 8

Published: March 26, 2019

Besides cardiomyocytes (CM), the heart contains numerous interstitial cell types which play key roles in repair, regeneration and disease, including fibroblast, vascular immune cells. However, a comprehensive understanding of this interactive community is lacking. We performed single-cell RNA-sequencing total non-CM fraction enriched (Pdgfra-GFP+) fibroblast lineage cells from murine hearts at days 3 7 post-sham or myocardial infarction (MI) surgery. Clustering >30,000 single identified >30 populations representing nine lineages, previously undescribed trajectory present both sham MI leading to uniquely activated state defined part by strong anti-WNT transcriptome signature. also uncovered novel myofibroblast subtypes expressing either pro-fibrotic anti-fibrotic signatures. Our data highlight non-linear dynamics myeloid lineages after cardiac injury, provide an entry point for deeper analysis homeostasis, inflammation, fibrosis, repair regeneration.

Language: Английский

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Cardiac monocytes and macrophages after myocardial infarction

Cardiovascular Research, Journal Year: 2019, Volume and Issue: 116(6), P. 1101 - 1112

Published: Dec. 12, 2019

Abstract Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have survival dramatically recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate failed translate into practice. Monocytes macrophages, pleiotropic cells innate immune system, are integral both initial inflammatory response injury wound healing many tissues, including heart. However, cell behaviour contributes mouse models, prompting experimental efforts modulate prevent development HF. Seminal work macrophage biology defined macrophages as monocyte-derived that comprised two populations, pro-inflammatory M1 reparative M2 investigations cardiac populations suggested they aligned well this model. more data, other demonstrate remarkable heterogeneity plasticity development, phenotype, function. These insights may explain non-specific immunosuppressive offer novel opportunities for therapeutic targeting HF AMI. Here, we summarize traditional monocyte-macrophage paradigm, evidence significance these AMI, potential relevance emerging refutes canonical models monocyte biology.

Language: Английский

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