Publications by authors named "Gabriel Courties"

45 Publications

Synovial macrophages: from ordinary eaters to extraordinary multitaskers.

Trends Immunol 2021 Apr 6. Epub 2021 Apr 6.

Institute for Regenerative Medicine and Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Montpellier, Montpellier, France.

Like other tissues, joints contain resident macrophages, and their diversity is only beginning to be characterized. Based on the highlights of recent studies, we discuss where current challenges lie and propose new avenues for future research in the osteoarticular field.
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http://dx.doi.org/10.1016/j.it.2021.03.002DOI Listing
April 2021

Novel insights into macrophage diversity in rheumatoid arthritis synovium.

Autoimmun Rev 2021 Mar 18;20(3):102758. Epub 2021 Jan 18.

INSERM UMR1238, Bone Sarcoma and Remodelling of Calcified Tissues, Nantes University, Nantes, France. Electronic address:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting joints and causing progressive damage and disability. Macrophages are of critical importance in the initiation and perpetuation of synovitis in RA, they can function as antigen presenting cells leading to T-cell dependent B-cell activation, assume a variety of inflammatory cell states with the production of destructive cytokines, but also contribute to tissue homeostasis/repair. The recent development of high-throughput technologies, including bulk and single cells RNA-sequencing, has broadened our understanding of synovial cell diversity, and opened novel perspectives to the discovery of new potential therapeutic targets in RA. In this review, we will focus on the relationship between the synovial macrophage infiltration and clinical disease severity and response to treatment. We will then provide a state-of-the-art picture of the biological roles of synovial macrophages and distinct macrophage subsets described in RA. Finally, we will review the effects of approved conventional and biologic drugs on the synovial macrophage component and highlight the therapeutic potential of future strategies to re-program macrophage phenotypes in RA.
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http://dx.doi.org/10.1016/j.autrev.2021.102758DOI Listing
March 2021

Multimodal imaging of bacterial-host interface in mice and piglets with endocarditis.

Sci Transl Med 2020 11;12(568)

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA 02114, USA.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill that colonizes the heart's valves. relies on virulence factors to evade therapeutics and the host's immune response, usurping the host's clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.
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http://dx.doi.org/10.1126/scitranslmed.aay2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818516PMC
November 2020

New insights into macrophage heterogeneity in rheumatoid arthritis.

Joint Bone Spine 2021 01 31;88(1):105091. Epub 2020 Oct 31.

IRMB, INSERM, University of Montpellier, Montpellier, France.

Rheumatoid arthritis (RA) is a prototypic autoimmune disease that primarily affects joints. Clinical studies and animal models evidenced that mononuclear phagocytes including monocytes and macrophages are crucial to RA pathogenesis, contributing to inflammation and destruction of cartilage and bone. The last decade of research has tremendously changed our view on the origin of tissue-resident macrophages. In light of the recent publications that reveal important phenotypic and functional heterogeneity among macrophages, it is of paramount importance to identify the synovial macrophage subsets that might amplify the inflammatory response or promote the restoration of tissue homeostasis. In this review, we highlight latest studies applying single-cell RNA sequencing that provide deeper insights in macrophage subsets and their putative functions within both human and mouse synovial joint tissue.
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http://dx.doi.org/10.1016/j.jbspin.2020.105091DOI Listing
January 2021

Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche.

Nat Biomed Eng 2020 11 5;4(11):1076-1089. Epub 2020 Oct 5.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid-polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
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http://dx.doi.org/10.1038/s41551-020-00623-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655681PMC
November 2020

Fluorescence microscopy tensor imaging representations for large-scale dataset analysis.

Sci Rep 2020 03 27;10(1):5632. Epub 2020 Mar 27.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Understanding complex biological systems requires the system-wide characterization of cellular and molecular features. Recent advances in optical imaging technologies and chemical tissue clearing have facilitated the acquisition of whole-organ imaging datasets, but automated tools for their quantitative analysis and visualization are still lacking. We have here developed a visualization technique capable of providing whole-organ tensor imaging representations of local regional descriptors based on fluorescence data acquisition. This method enables rapid, multiscale, analysis and virtualization of large-volume, high-resolution complex biological data while generating 3D tractographic representations. Using the murine heart as a model, our method allowed us to analyze and interrogate the cardiac microvasculature and the tissue resident macrophage distribution and better infer and delineate the underlying structural network in unprecedented detail.
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http://dx.doi.org/10.1038/s41598-020-62233-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101442PMC
March 2020

Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge.

Immunity 2019 11 12;51(5):899-914.e7. Epub 2019 Nov 12.

Center for Systems Biology, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA; Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNɣ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.
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http://dx.doi.org/10.1016/j.immuni.2019.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892583PMC
November 2019

Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells.

Nat Med 2019 11 7;25(11):1761-1771. Epub 2019 Nov 7.

Center for Systems Biology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER; Lepr mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
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http://dx.doi.org/10.1038/s41591-019-0633-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858591PMC
November 2019

Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping.

Cell Stem Cell 2019 Oct 3;25(4):570-583.e7. Epub 2019 Jul 3.

Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge St., Boston, MA 02114, USA; Harvard Stem Cell Institute, 7 Divinity Ave., Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Stromal cell populations that maintain hematopoietic stem and progenitor cells (HSPCs) are generally characterized in steady-state conditions. Here, we report a comprehensive atlas of bone marrow stromal cell subpopulations under homeostatic and stress conditions using mass cytometry (CyTOF)-based single-cell protein analysis. We identified 28 subsets of non-hematopoietic cells during homeostasis, 14 of which expressed hematopoietic regulatory factors. Irradiation-based conditioning for HSPC transplantation led to the loss of most of these populations, including the LeptinR and Nestin subsets. In contrast, a subset expressing Ecto-5'-nucleotidase (CD73) was retained and a specific CD73NGFR population expresses high levels of cytokines during homeostasis and stress. Genetic ablation of CD73 compromised HSPC transplantation in an acute setting without long-term changes in bone marrow HSPCs. Thus, this protein-based expression mapping reveals distinct sets of stromal cells in the bone marrow and how they change in clinically relevant stress settings to contribute to early stages of hematopoietic regeneration.
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http://dx.doi.org/10.1016/j.stem.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778015PMC
October 2019

Glucocorticoids Regulate Bone Marrow B Lymphopoiesis After Stroke.

Circ Res 2019 04;124(9):1372-1385

From the Center for Systems Biology and Radiology Department (G.C., V.F., L.H., F.H., M.J.S., Y.S., C.E., M.H., S.C., D.R., M.J.P., F.K.S., M.N.), Harvard Medical School, Boston.

Rationale: After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow.

Objective: To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke.

Methods And Results: We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88 and TLR4 mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers.

Conclusions: Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.314518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483874PMC
April 2019

Delivery of miR-146a to Ly6C Monocytes Inhibits Pathogenic Bone Erosion in Inflammatory Arthritis.

Theranostics 2018 13;8(21):5972-5985. Epub 2018 Nov 13.

IRMB, INSERM, University of Montpellier, Montpellier, France.

Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6C and non-classical Ly6C monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a mice and assessed the therapeutic potential of miR-146a mimics delivery to Ly6C monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a mice. We showed that the expression of miR-146a is reduced in the Ly6C subset of CIA mice and in the analogous monocyte subset (CD14CD16) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation and bone erosion . delivery of miR-146a to Ly6C monocytes, and not to Ly6C monocytes, rescues bone erosion in miR-146a arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a Ly6C monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6C, and not Ly6C, monocytes into osteoclasts under arthritic conditions. Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6C monocytes to prevent joint destruction while sparing inflammation in arthritis.
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http://dx.doi.org/10.7150/thno.29313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299444PMC
September 2019

Quantitative Imaging of Tumor-Associated Macrophages and Their Response to Therapy Using Cu-Labeled Macrin.

ACS Nano 2018 12 11;12(12):12015-12029. Epub 2018 Dec 11.

Center for Systems Biology , Massachusetts General Hospital Research Institute , Boston , Massachusetts 02114 , United States.

Tumor-associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors. By combining PET with high-resolution in vivo confocal microscopy and ex vivo imaging of optically cleared tissue, we found that Macrin was taken up by macrophages with >90% selectivity. Uptake correlated with the content of macrophages in both healthy tissue and tumors ( R > 0.9) and showed striking heterogeneity in the TAM content of an orthotopic and immunocompetent mouse model of lung carcinoma. In a proof-of-principle application, we imaged Macrin to monitor the macrophage response to neo-adjuvant therapy, using a panel of chemotherapeutic and γ-irradiation regimens. Multiple treatments elicited 180-650% increase in TAMs. Imaging identified especially TAM-rich tumors thought to exhibit enhanced permeability and retention of nanotherapeutics. Indeed, these TAM-rich tumors accumulated >700% higher amounts of a model poly(d,l-lactic- co-glycolic acid)- b-polyethylene glycol (PLGA-PEG) therapeutic nanoparticle compared to TAM-deficient tumors, suggesting that imaging may guide patient selection into nanomedicine trials. In an orthotopic breast cancer model, chemoradiation enhanced TAM and Macrin accumulation in tumors, which corresponded to the improved delivery and efficacy of two model nanotherapies, PEGylated liposomal doxorubicin and a TAM-targeted nanoformulation of the toll-like receptor 7/8 agonist resiquimod (R848). Thus, Macrin imaging offers a selective and translational means to quantify TAMs and inform therapeutic decisions.
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http://dx.doi.org/10.1021/acsnano.8b04338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482841PMC
December 2018

Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration.

Nat Neurosci 2018 09 27;21(9):1209-1217. Epub 2018 Aug 27.

Center for Systems Biology, Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.
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http://dx.doi.org/10.1038/s41593-018-0213-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148759PMC
September 2018

Imaging the Vascular Bone Marrow Niche During Inflammatory Stress.

Circ Res 2018 08;123(4):415-427

From the Department of Imaging, Center for Systems Biology (K.V., D.R., H.-Y.K., G.G., G.W., L.H., F.F.H., V.F., R.N., F.H., Y.J., C.V., R.W., C.P.L., F.K.S., M.N.).

Rationale: Inflammatory stress induced by exposure to bacterial lipopolysaccharide causes hematopoietic stem cell expansion in the bone marrow niche, generating a cellular immune response. As an integral component of the hematopoietic stem cell niche, the bone marrow vasculature regulates the production and release of blood leukocytes, which protect the host against infection but also fuel inflammatory diseases.

Objective: We aimed to develop imaging tools to explore vascular changes in the bone marrow niche during acute inflammation.

Methods And Results: Using the TLR (Toll-like receptor) ligand lipopolysaccharide as a prototypical danger signal, we applied multiparametric, multimodality and multiscale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. In response to lipopolysaccharide, ex vivo flow cytometry and histology showed vascular changes to the bone marrow niche. Specifically, proliferating endothelial cells gave rise to new vasculature in the bone marrow during hypoxic conditions. We studied these vascular changes with complementary intravital microscopy and positron emission tomography/magnetic resonance imaging. Fluorescence and positron emission tomography integrin αVβ3 imaging signal increased during lipopolysaccharide-induced vascular remodeling. Vascular leakiness, quantified by albumin-based in vivo microscopy and magnetic resonance imaging, rose when neutrophils departed and hematopoietic stem and progenitor cells proliferated more vigorously.

Conclusions: Introducing a tool set to image bone marrow either with cellular resolution or noninvasively within the entire skeleton, this work sheds light on angiogenic responses that accompany emergency hematopoiesis. Understanding and monitoring bone marrow vasculature may provide a key to unlock therapeutic targets regulating systemic inflammation.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202141PMC
August 2018

Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF neutrophils.

Science 2017 12;358(6367)

Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients ( = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecF neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecF neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.
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http://dx.doi.org/10.1126/science.aal5081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343476PMC
December 2017

Macrophages Facilitate Electrical Conduction in the Heart.

Cell 2017 04;169(3):510-522.e20

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
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http://dx.doi.org/10.1016/j.cell.2017.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474950PMC
April 2017

Motion characterization scheme to minimize motion artifacts in intravital microscopy.

J Biomed Opt 2017 03;22(3):36005

Richard B. Simches Research Center, Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States.

Respiratory- and cardiac-induced motion artifacts pose a major challenge for in vivo optical imaging, limiting the temporal and spatial imaging resolution in fluorescence laser scanning microscopy. Here, we present an imaging platform developed for in vivo characterization of physiologically induced axial motion. The motion characterization system can be straightforwardly implemented on any conventional laser scanning microscope and can be used to evaluate the effectiveness of different motion stabilization schemes. This method is particularly useful to improve the design of novel tissue stabilizers and to facilitate stabilizer positioning in real time, therefore facilitating optimal tissue immobilization and minimizing motion induced artifacts.
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http://dx.doi.org/10.1117/1.JBO.22.3.036005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333764PMC
March 2017

Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease.

Nat Commun 2017 01 16;8:14064. Epub 2017 Jan 16.

Center for Systems Biology and Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology.
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http://dx.doi.org/10.1038/ncomms14064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241815PMC
January 2017

Myeloperoxidase Inhibition Improves Ventricular Function and Remodeling After Experimental Myocardial Infarction.

JACC Basic Transl Sci 2016 Dec 26;1(7):633-643. Epub 2016 Dec 26.

Center for Systems Biology, and the Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

PF-1355 is an oral myeloperoxidase (MPO) inhibitor that successfully decreased elevated MPO activity in mouse myocardial infarction models. Short duration PF-1355 treatment for 7 days decreased the number of inflammatory cells and attenuated left ventricular dilation. Cardiac function and remodeling improved when treatment was increased to 21 days. Better therapeutic effect was further achieved with early compared with delayed treatment initiation (1 h vs. 24 h after infarction). In conclusion, PF-1355 treatment protected a mouse heart from acute and chronic effects of MI, and this study paves the way for future translational studies investigating this class of drugs in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.jacbts.2016.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113523PMC
December 2016

Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.

Circ Res 2016 Sep 21;119(7):853-64. Epub 2016 Jul 21.

From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).

Rationale: Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear.

Objective: This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.

Methods And Results: Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05).

Conclusions: Myocardial failure is influenced by an altered myeloid cell repertoire.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378496PMC
September 2016

RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

Sci Transl Med 2016 06;8(342):342ra80

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE(-/-) mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)-targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI.
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http://dx.doi.org/10.1126/scitranslmed.aaf1435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125383PMC
June 2016

Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis.

Circ Res 2015 Oct 22;117(10):835-45. Epub 2015 Sep 22.

From the Center for Systems Biology, Department of Radiology (Y.-X.Y., G.C., E.J.K., G.R.W., Y.I., R.W., F.K.S., M.N.) and Division of Cardiology (A.T.), Massachusetts General Hospital and Harvard Medical School, Boston; Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY (C.C., J.T., C.P.-M., V.M., S.I., Z.A.F., W.J.M.M.); Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging (T.B., C.B.J., A.K.) and Departments of Clinical Endocrinology PE and Surgery C (U.K.), Rigshospitalet, National University Hospital & University of Copenhagen, Copenhagen, Denmark; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L., M.F.D.C.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D., A.P.B., M.F.D.C.); and Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (W.J.M.M.).

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention.

Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis.

Methods And Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta.

Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.307024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619168PMC
October 2015

Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction.

Circulation 2015 Nov 10;132(20):1880-90. Epub 2015 Sep 10.

From Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston, MA (H.B.S., T.H., M.H., P.D., G.C., M.S., G.R.W., B.T., Y.I., Y.S., R.W., F.K.S., M.N.); Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.); and Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (P.L.).

Background: Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood.

Methods And Results: With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow's hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE(-/-) mice with atherosclerosis.

Conclusions: The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.016160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651795PMC
November 2015

Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.

Cell Stem Cell 2015 May;16(5):477-87

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address:

Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2(+)CD150(+)CD48(-) LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2(-)CD150(+)CD48(-) LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2(+) HSPC emergence. Mtg16(-/-) mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
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http://dx.doi.org/10.1016/j.stem.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426344PMC
May 2015

Macrophages retain hematopoietic stem cells in the spleen via VCAM-1.

J Exp Med 2015 Apr 23;212(4):497-512. Epub 2015 Mar 23.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)(+) macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE(-/-) mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques.
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http://dx.doi.org/10.1084/jem.20141642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387283PMC
April 2015

Ischemic stroke activates hematopoietic bone marrow stem cells.

Circ Res 2015 Jan 31;116(3):407-17. Epub 2014 Oct 31.

From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (G.C., H.B.S., T.H., Y.Y., Y.S., P.D., J.S., R.W., F.K.S., M.N.); Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital/Harvard Medical School, Charlestown (F.H., Y.W., M.A.M.); Center for Regenerative Medicine, Massachusetts General Hospital, Boston (N.S., D.T.S.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).

Rationale: The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood.

Objective: To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells.

Methods And Results: Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (P<0.05 versus pre tMCAO). Flow cytometry and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (P<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (P<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (P<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the β3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51).

Conclusions: Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.305207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312511PMC
January 2015

Chronic variable stress activates hematopoietic stem cells.

Nat Med 2014 Jul 22;20(7):754-758. Epub 2014 Jun 22.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.

Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.
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http://dx.doi.org/10.1038/nm.3589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087061PMC
July 2014

Silencing of CCR2 in myocarditis.

Eur Heart J 2015 Jun 20;36(23):1478-88. Epub 2014 Jun 20.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA

Background: Myocarditis is characterized by inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function. Monocytes are the most prominent population of accumulating leucocytes. We investigated whether in vivo administration of nanoparticle-encapsulated siRNA targeting chemokine (C-C motif) receptor 2 (CCR2)-a chemokine receptor crucial for leucocyte migration in humans and mice--reduces inflammation in autoimmune myocarditis.

Methods And Results: In myocardium of patients with myocarditis, CCL2 mRNA levels and CCR2(+) cells increased (P < 0.05), motivating us to pursue CCR2 silencing. Flow cytometric analysis showed that siRNA silencing of CCR2 (siCCR2) reduced the number of Ly6C(high) monocytes in hearts of mice with acute autoimmune myocarditis by 69% (P < 0.05), corroborated by histological assessment. The nanoparticle-delivered siRNA was not only active in monocytes but also in bone marrow haematopoietic progenitor cells. Treatment with siCCR2 reduced the migration of bone marrow granulocyte macrophage progenitors into the blood. Cellular magnetic resonance imaging (MRI) after injection of macrophage-avid magnetic nanoparticles detected myocarditis and therapeutic effects of RNAi non-invasively. Mice with acute myocarditis showed enhanced macrophage MRI contrast, which was prevented by siCCR2 (P < 0.05). Follow-up MRI volumetry revealed that siCCR2 treatment improved ejection fraction (P < 0.05 vs. control siRNA-treated mice).

Conclusion: This study highlights the importance of CCR2 in the pathogenesis of myocarditis. In addition, we show that siCCR2 affects leucocyte progenitor trafficking. The data also point to a novel therapeutic strategy for the treatment of myocarditis.
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http://dx.doi.org/10.1093/eurheartj/ehu225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465633PMC
June 2015

Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction.

Circ Res 2014 Jul 1;115(2):284-95. Epub 2014 May 1.

From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).

Rationale: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation.

Objective: Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction.

Methods And Results: Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation.

Conclusions: In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.303567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082439PMC
July 2014

In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing.

J Am Coll Cardiol 2014 Apr 18;63(15):1556-66. Epub 2013 Dec 18.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Objectives: The aim of this study was to test whether silencing of the transcription factor interferon regulatory factor 5 (IRF5) in cardiac macrophages improves infarct healing and attenuates post-myocardial infarction (MI) remodeling.

Background: In healing wounds, the M1 toward M2 macrophage phenotype transition supports resolution of inflammation and tissue repair. Persistence of inflammatory M1 macrophages may derail healing and compromise organ functions. The transcription factor IRF5 up-regulates genes associated with M1 macrophages.

Methods: Here we used nanoparticle-delivered small interfering ribonucleic acid (siRNA) to silence IRF5 in macrophages residing in MIs and in surgically-induced skin wounds in mice.

Results: Infarct macrophages expressed high levels of IRF5 during the early inflammatory wound-healing stages (day 4 after coronary ligation), whereas expression of the transcription factor decreased during the resolution of inflammation (day 8). Following in vitro screening, we identified an siRNA sequence that, when delivered by nanoparticles to wound macrophages, efficiently suppressed expression of IRF5 in vivo. Reduction of IRF5 expression, a factor that regulates macrophage polarization, reduced expression of inflammatory M1 macrophage markers, supported resolution of inflammation, accelerated cutaneous and infarct healing, and attenuated development of post-MI heart failure after coronary ligation as measured by protease targeted fluorescence molecular tomography-computed tomography imaging and cardiac magnetic resonance imaging (p < 0.05).

Conclusions: This work identified a new therapeutic avenue to augment resolution of inflammation in healing infarcts by macrophage phenotype manipulation. This therapeutic concept may be used to attenuate post-MI remodeling and heart failure.
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http://dx.doi.org/10.1016/j.jacc.2013.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992176PMC
April 2014