Macrophages are ubiquitous cells that reside in all major tissues. Counter to long-held beliefs, we now know that resident macrophages in many organs are seeded during embryonic development and ...self-renew independently from blood monocytes. Under inflammatory conditions, those tissue macrophages are joined and sometimes replaced by recruited monocyte-derived macrophages. Macrophage function in steady state and disease depends on not only their developmental origin but also the tissue environment. Here, we discuss the ontogeny, function, and interplay of tissue-resident and monocyte-derived macrophages in various organs contributing to the development and progression of cardiovascular disease.
Monocytes in myocardial infarction Dutta, Partha; Nahrendorf, Matthias
Arteriosclerosis, thrombosis, and vascular biology
35, Številka:
5
Journal Article
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Myocardial infarction (MI) is the leading cause of death in developed countries. Though timely revascularization of the ischemic myocardium and current standard therapy reduce acute mortality after ...MI, long-term morbidity and mortality remain high. During the first 1 to 2 weeks after MI, tissues in the infarcted myocardium undergo rapid turnover, including digestion of extracellular matrix and fibrosis. Post-MI repair is crucial to survival. Monocytes recruited to the infarcted myocardium remove debris and facilitate the repair process. However, exaggerated inflammation may also impede healing, as demonstrated by the association between elevated white blood cell count and in-hospital mortality after MI. Monocytes produced in the bone marrow and spleen enter the blood after MI and are recruited to the injured myocardium in 2 phases. The first phase is dominated by Ly-6c(high) monocytes and the second phase by Ly-6c(low) monocytes. Yet the number of Ly6C(low) monocytes recruited to the infarct is much lower, and Ly6C(high) monocytes can differentiate to Ly6C(low) macrophages in later healing stages. Understanding the signals regulating monocytosis after MI will help design new therapies to facilitate cardiac healing and limit heart failure.
Macrophages and Cardiovascular Health Frodermann, Vanessa; Nahrendorf, Matthias
Physiological reviews,
10/2018, Letnik:
98, Številka:
4
Journal Article
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Research during the last decade has generated numerous insights on the presence, phenotype, and function of myeloid cells in cardiovascular organs. Newer tools with improved detection sensitivities ...revealed sizable populations of tissue-resident macrophages in all major healthy tissues. The heart and blood vessels contain robust numbers of these cells; for instance, 8% of noncardiomyocytes in the heart are macrophages. This number and the cell's phenotype change dramatically in disease conditions. While steady-state macrophages are mostly monocyte independent, macrophages residing in the inflamed vascular wall and the diseased heart derive from hematopoietic organs. In this review, we will highlight signals that regulate macrophage supply and function, imaging applications that can detect changes in cell numbers and phenotype, and opportunities to modulate cardiovascular inflammation by targeting macrophage biology. We strive to provide a systems-wide picture, i.e., to focus not only on cardiovascular organs but also on tissues involved in regulating cell supply and phenotype, as well as comorbidities that promote cardiovascular disease. We will summarize current developments at the intersection of immunology, detection technology, and cardiovascular health.
Advancing biomedical imaging Weissleder, Ralph; Matthias Nahrendorf
Proceedings of the National Academy of Sciences - PNAS,
11/2015, Letnik:
112, Številka:
47
Journal Article
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Imaging reveals complex structures and dynamic interactive processes, located deep inside the body, that are otherwise difficult to decipher. Numerous imaging modalities harness every last inch of ...the energy spectrum. Clinical modalities include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, and light-based methods endoscopy and optical coherence tomography (OCT). Research modalities include various light microscopy techniques (confocal, multiphoton, total internal reflection, superresolution fluorescence microscopy), electron microscopy, mass spectrometry imaging, fluorescence tomography, bioluminescence, variations of OCT, and optoacoustic imaging, among a few others. Although clinical imaging and research microscopy are often isolated from one another, we argue that their combination and integration is not only informative but also essential to discovering new biology and interpreting clinical datasets in which signals invariably originate from hundreds to thousands of cells per voxel.
Cardiovascular diseases claim more lives worldwide than any other. Etiologically, the dominant trajectory involves atherosclerosis, a chronic inflammatory process of lipid-rich lesion growth in the ...vascular wall that can cause life-threatening myocardial infarction (MI). Those who survive MI can develop congestive heart failure, a chronic condition of inadequate pump activity that is frequently fatal. Leukocytes (white blood cells) are important participants at the various stages of cardiovascular disease progression and complication. This Review will discuss leukocyte function in atherosclerosis, MI, and heart failure.
Monocytes and macrophages are innate immune cells that reside and accumulate in the healthy and injured heart. The cells and their subsets pursue distinct functions in steady-state and disease, and ...their tenure may range between hours and months. Some subsets are highly inflammatory, whereas others support tissue repair. This review discusses current concepts of lineage relationships and crosstalk of systems, highlights open questions, and describes tools for studying monocyte and macrophage subsets in the murine and human heart.
The increasing use of single-cell immune profiling and advanced microscopic imaging technologies has deepened our understanding of the cardiac immune system, confirming that the heart contains a ...broad repertoire of innate and adaptive immune cells. Leucocytes found in the healthy heart participate in essential functions to preserve cardiac homeostasis, not only by defending against pathogens but also by maintaining normal organ function. In pathophysiological conditions, cardiac inflammation is implicated in healing responses after ischaemic or non-ischaemic cardiac injury. The aim of this review is to provide a concise overview of novel methodological advancements to the non-expert readership and summarize novel findings on immune cell heterogeneity and functions in cardiac disease with a focus on myocardial infarction as a prototypic example. In addition, we will briefly discuss how biological sex modulate the cardiac immune response. Finally, we will highlight emerging concepts for novel therapeutic applications, such as targeting immunometabolism and nanomedicine.
Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac ...aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic
F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for ...arrhythmia. Many of the underlying conditions that give rise to arrhythmia - including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure - can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.
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