Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart

Heo, Gyu Seong; Kopecky, Benjamin; Sultan, Deborah; Ou, Monica H.; Feng, Guoshuai; Bajpai, Geetika; Zhang, Xiaohui; Luehmann, Hannah; Detering, Lisa; Su, Yi; Leuschner, Florian; Combadière, Christophe; Kreisel, Daniel; Gropler, Robert J.; Brody, Steven L.; Liu, Yongjian; Lavine, Kory J.

doi:10.1161/circresaha.118.314030

Cited by 105 publications

(84 citation statements)

References 40 publications

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“…In addition, a recent study using scRNA-Seq demonstrated the existence of multiple populations of resident and recruited macrophages in mouse lung airspace under healthy and acute inflammatory conditions; these macrophage populations exhibited distinct transcriptional profiles relevant to the inflammatory process [33]. As in the cardiac study [32], these macrophage populations were identified using unsupervised clustering and analysis of classical inflammatory and reparative markers [33]. Similar studies in atherosclerosis in mice and steady-state human liver, among other tissues, have found similar results: macrophages have been grouped into multiple and distinct populations using unsupervised clustering based on gene expression profiles; based on known phenotypic marker genes coupled to experimental analysis relying on the reduction or exacerbation of disease phenotypes, such macrophage populations were grouped to reflect distinct presumed functions [28,29].…”

Section: Single-cell Transcriptomics Reveals Macrophage Subpopulationmentioning

confidence: 81%

“…Specifically, although a small population of resident CCR2 + macrophages could be identified even in uninjured hearts, the increase in visualized CCR2 signal after MI in mice was dramatic and could be easily distinguished from baseline. In addition, this probe was capable of detecting CCR2 + monocytes and macrophages in humans post-MI and in chronic ischemic cardiomyopathy, thus providing proof of concept for the development of putative biomarkers and targeted treatments based on CCR2 [32].…”

Section: Single-cell Transcriptomics Reveals Macrophage Subpopulationmentioning

confidence: 98%

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Macrophage Plasticity and Function in the Eye and Heart

Wang

Koenig

Lavine

et al. 2019

Trends in Immunology

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Macrophages are important mediators of inflammation and tissue remodeling. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in homeostasis and disease. In addition, their plasticity enables them to perform a variety of functions in response to changing tissue contexts, such as those imposed by aging. These qualities make macrophages particularly intriguing cells given their dichotomous role in protecting against, or accelerating, diseases of the cardiovascular system and the eye, two tissues that are particularly susceptible to the effects of aging. We review novel perspectives on macrophage biology, as informed by recent studies detailing the diversity of macrophage identity and function, as well as mechanisms influencing macrophage behavior that might offer opportunities for new therapeutic strategies. New Insights into Macrophage Lineage, Function, and Plasticity in Health and Disease Highlights Recent studies combining single-cell transcriptomics, imaging, and functional assays provide mechanistic validation of prior observations indicating that murine macrophage heterogeneity contributes to diverse roles in healthy tissue and during disease response.

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Section: Single-cell Transcriptomics Reveals Macrophage Subpopulationmentioning

confidence: 81%

Section: Single-cell Transcriptomics Reveals Macrophage Subpopulationmentioning

confidence: 98%

Macrophage Plasticity and Function in the Eye and Heart

Wang

Koenig

Lavine

et al. 2019

Trends in Immunology

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“…Previously, we reported the capacity of a targeted PET tracer to quantify the CCR2-specific inflammation burden in multiple animal models using ECL1i peptide through 64 Cu or 68 Ga radiolabel (7)(8)(9). The PET signal intensity in inflammatory tissues was corroborated by molecular characterization of CCR2 expression and correlated with disease progression and regression.…”

Section: Introductionmentioning

confidence: 85%

Targeted PET Imaging of Chemokine Receptor 2–Positive Monocytes and Macrophages in the Injured Heart

Heo

Bajpai

et al. 2020

J Nucl Med

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Proinflammatory macrophages are important mediators of inflammation following myocardial infarction and allograft injury following heart transplantation. The aim of this study was to image the recruitment of proinflammatory chemokine receptor 2+ (CCR2+) cells in multiple heart injury models. Methods: 64 Cu-DOTA-ECL1i PET was used to image CCR2+ monocytes/macrophages in heart transplantation mouse model. Flow cytometry was performed to characterize CCR2+ cells. Autoradiography on human heart specimen was conducted to confirm binding specificity. 64 Cu-/ 68 Ga-DOTA-ECL1i were compared in ischemia/reperfusion injury mouse model. Results: 64 Cu-DOTA-ECL1i showed sensitive and specific detection of CCR2+ cells in all tested mouse models with comparable efficacy to 68 Ga-DOTA-ECL1i. Flow cytometry demonstrated specific expression of CCR2 on monocytes/macrophages. The tracer binds to human CCR2. Conclusion: This work establishes the utility of 64 Cu-DOTA-ECL1i to image CCR2+ monocytes/macrophages in mouse models and provides the requisite pre-clinical information to translate the targeted clinical grade CCR2 imaging probe for clinical investigation of heart diseases.

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“…The TIMD4 + and TIMD4 - subgroups were reduced in the early phase post MI but gradually increased via self-renewal 71 . 68 Ga-DOTA-ECL1i, a PET radiotracer, could specifically bind to CCR2 + monocytes/macrophages, and the signal was correlated with CCR2 + abundance, which provided an effective molecular imaging method to noninvasively visualize the recruitment of monocytes and macrophages to the infarct heart 72 .…”

Section: Immune Cellsmentioning

confidence: 99%

The Roles of Noncardiomyocytes in Cardiac Remodeling

Yang

Liu

et al. 2020

Int. J. Biol. Sci.

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Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

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Molecular Imaging Visualizes Recruitment of Inflammatory Monocytes and Macrophages to the Injured Heart

Cited by 105 publications

References 40 publications

Macrophage Plasticity and Function in the Eye and Heart

Macrophage Plasticity and Function in the Eye and Heart

Targeted PET Imaging of Chemokine Receptor 2–Positive Monocytes and Macrophages in the Injured Heart

The Roles of Noncardiomyocytes in Cardiac Remodeling

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