The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis (original) (raw)
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The Macrophage in Cardiac Homeostasis and Disease
Journal of the American College of Cardiology, 2018
Macrophages are integral components of cardiac tissue and exert profound effects on the healthy and diseased heart. Paradigm shifting studies using advanced molecular techniques have revealed significant complexity within these macrophage populations that reside in the heart. In this final of a 4-part review series covering the macrophage in cardiovascular disease, the authors review the origins, dynamics, cell surface markers, and respective functions of each cardiac macrophage subset identified to date, including in the specific scenarios of myocarditis and after myocardial infarction. Looking ahead, a deeper understanding of the diverse and often dichotomous functions of cardiac macrophages will be essential for the development of targeted therapies to mitigate injury and orchestrate recovery of the diseased heart. Moreover, as macrophages are critical for cardiac healing, they are an emerging focus for therapeutic strategies aimed at minimizing cardiomyocyte death, ameliorating pathological cardiac remodeling, and for treating heart failure and after myocardial infarction.
Circulation Journal, 2020
macrophages participate in the removal of pathogens, debris clearance, and neovascularization. 6 M2 macrophages, also called anti-inflammatory macrophages, are polarized by Th2 cytokines and characterized by the production of high levels of anti-inflammatory cytokines and pro-fibrogenic factors. 6,11 There are 3 subtypes of M2 macrophages: M2a, M2b, and M2c. 9,12,13 All M2 macrophage subtypes are immunosuppressive, but are distinguished by marker expression, induction factors, the production of specific cytokines and chemokines, and their biological function. 14,15 The main biological functions of M2a, M2b, and M2c macrophages are wound healing, immunological regulation, and efferocytosis, respectively. 13,16 However, Mosser and Edwards 13 considered the M1/M2 classification to be an oversimplification and suggested a functional classification of macrophages that distinguishes between classical, regulatory and reparative subpopulations of macrophages. In this classification, M2b macrophages C ardiac fibrosis is associated with nearly all forms of heart disease, and there are limited treatment options. 1,2 This condition is characterized by the excessive deposition of extracellular matrix (ECM), typically collagen. The proliferation of cardiac fibroblasts (CFs) and their conversion into synthetic myofibroblasts (MFs) are hallmarks of this process. There is accumulating evidence that the interaction of macrophages with fibroblasts is crucial to the development of fibrosis. 3-6 Cardiac macrophages, including resident tissue macrophages and recruited monocytes from the bone marrow, 7 are highly heterogeneous and exhibit functional and phenotypic versatility. They can be divided into classically activated macrophages (M1) and alternatively activated macrophages (M2). 8 M1 macrophages, also called proinflammatory macrophages, are induced by Th1 cytokines and by lipopolysaccharide (LPS) recognition, and release large amounts of pro-inflammatory cytokines. 9,10 M1
Targeting Immune-Fibroblast Crosstalk in Myocardial Infarction and Cardiac Fibrosis
Inflammation and tissue fibrosis co-exist and are causally linked to organ dysfunction. However, the molecular mechanisms driving immune-fibroblast crosstalk in human cardiac disease remains unexplored and there are currently no therapeutics to target fibrosis. Here, we performed multi-omic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in 38 donors, acutely infarcted, and chronically failing human hearts. We identified a disease-associated fibroblast trajectory marked by cell surface expression of fibroblast activator protein (FAP), which diverged into distinct myofibroblasts and pro-fibrotic fibroblast populations, the latter resembling matrifibrocytes. Pro-fibrotic fibroblasts were transcriptionally similar to cancer associated fibroblasts and expressed high levels of collagens and periostin (POSTN), thymocyte differentiation antigen 1 (THY-1), and endothelin receptor A (EDNRA) predicted to be driven by a RUNX1 gene regulatory network. We asse...
Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction
Nature Immunology, 2018
Macrophages promote both injury and repair following myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping and singlecell transcriptomics to demonstrate that at steady state, TIMD4 + LYVE1 + MHC-II lo CCR2 − resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4 − LYVE1 − MHC-II hi CCR2 − macrophages and fully replaced TIMD4 − LYVE1 − MHC-II hi CCR2 + macrophages, revealing a hierarchy of monocyte contribution Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy
Proceedings of the National Academy of Sciences of the United States of America, 2018
Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and s...
Resident Cardiac Macrophages Mediate Adaptive Myocardial Remodeling
2021
SummaryCardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identify an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4) dependent pathway that controlled...
Proceedings of the National Academy of Sciences, 2014
Significance This study addresses a fundamentally important and widely debated issue in the field of inflammation, which is why inflammation can be simultaneously deleterious after injury and yet is essential for tissue repair. Recently, an important new paradigm has emerged in the macrophage field: Organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. In this article, we use a new model of cardiac injury and show that distinct macrophage populations derived from embryonic and adult lineages are important determinants of tissue repair and inflammation, respectively. Our data suggest that therapeutics, which inhibit monocyte-derived macrophages and/or selectively harness the function of embryonic-derived macrophages, may serve as novel treatments for heart failure.
The human heart contains distinct macrophage subsets with divergent origins and functions
Nature medicine, 2018
Paradigm-shifting studies in the mouse have identified tissue macrophage heterogeneity as a critical determinant of immune responses. In contrast, surprisingly little is known regarding macrophage heterogeneity in humans. Macrophages within the mouse heart are partitioned into CCR2- and CCR2+ subsets with divergent origins, repopulation mechanisms, and functions. Here, we demonstrate that the human myocardium also contains distinct subsets of CCR2- and CCR2+ macrophages. Analysis of sex-mismatched heart transplant recipients revealed that CCR2- macrophages are a tissue-resident population exclusively replenished through local proliferation, whereas CCR2+ macrophages are maintained through monocyte recruitment and proliferation. Moreover, CCR2- and CCR2+ macrophages have distinct functional properties, analogous to reparative CCR2- and inflammatory CCR2+ macrophages in the mouse heart. Clinically, CCR2+ macrophage abundance is associated with left ventricular remodeling and systolic ...
Abstract 55: Opposing Roles Of Distinct Macrophage Lineages In Heart Failure And Cardiac Recovery
Circulation Research, 2014
Why inflammation is simultaneously deleterious following injury and essential for tissue repair continues to be fundamentally important and debated question. Recently, a new paradigm has emerged in the macrophage field: that organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities following injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared to the adult, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition in the neonatal and adult heart represents a key determinant of cardiac recovery. To test this hypothesis, we generated a novel cardiomyocyte ablation model and demonstrated that following injury neonatal mice expand a population of resident cardiac macrophages derived from em...
Macrophages dictate the progression and manifestation of hypertensive heart disease
Background: Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling. Methods and results: We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p b 0.05), and reduced cardiac fibrosis by 75%, compared with controls (p = 0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macro-phages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion , for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p b 0.05), and a 13% in LV mass (p = 0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibro-sis by 80% (p = 0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%). Conclusions: Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.