Publications by authors named "Filip K Swirski"

178 Publications

Prosaposin mediates inflammation in atherosclerosis.

Sci Transl Med 2021 Mar;13(584)

Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell-specific nanobiologics in apolipoprotein E-deficient () mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages' inflammatory activity. By investigating transcriptome modifications, we identified , a gene encoding the lysosomal protein prosaposin, as closely related with mTOR signaling. Subsequent in vitro experiments revealed that inhibition suppressed both glycolysis and oxidative phosphorylation. Transplantation of bone marrow to low-density lipoprotein receptor knockout () mice led to a reduction in atherosclerosis development and plaque inflammation. Last, we confirmed the relationship between expression and inflammation in human carotid atherosclerotic plaques. Our findings provide mechanistic insights into the development of atherosclerosis and identify prosaposin as a potential therapeutic target.
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http://dx.doi.org/10.1126/scitranslmed.abe1433DOI Listing
March 2021

Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis.

Cell 2021 Mar 25;184(5):1348-1361.e22. Epub 2021 Feb 25.

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

Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2 cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
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http://dx.doi.org/10.1016/j.cell.2021.01.049DOI Listing
March 2021

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections.

Nat Commun 2021 02 18;12(1):1112. Epub 2021 Feb 18.

Department of Surgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123 epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
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http://dx.doi.org/10.1038/s41467-021-21310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893044PMC
February 2021

ESC William Harvey Lecture on Basic Science 2020.

Authors:
Filip K Swirski

Eur Heart J 2020 12;41(46):4373-4374

Professor of Radiology at Harvard Medical School and a Massachusetts General Hospital Research Scholar delivered the lecture on: Modifiable risk factors and cardiovascular disease.

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http://dx.doi.org/10.1093/eurheartj/ehaa766DOI Listing
December 2020

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.

Basic Res Cardiol 2020 12 9;115(6):78. Epub 2020 Dec 9.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, 55 Hugstetter St, 79106, Freiburg, Germany.

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
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http://dx.doi.org/10.1007/s00395-020-00838-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725697PMC
December 2020

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

Imaging Cardiovascular and Lung Macrophages With the Positron Emission Tomography Sensor Cu-Macrin in Mice, Rabbits, and Pigs.

Circ Cardiovasc Imaging 2020 10 20;13(10):e010586. Epub 2020 Oct 20.

Biomedical Engineering and Imaging Institute (A.E.M., M.M.T.v.L., M.L.S., C.C., P.M.R., G.S., C.P.-M., A.J.P.T., Y.C.T., K.S., E.M.v.L., E.D.K., A.M.S., W.J.M.M.), Icahn School of Medicine at Mount Sinai, New York, NY.

Background: Macrophages, innate immune cells that reside in all organs, defend the host against infection and injury. In the heart and vasculature, inflammatory macrophages also enhance tissue damage and propel cardiovascular diseases.

Methods: We here use in vivo positron emission tomography (PET) imaging, flow cytometry, and confocal microscopy to evaluate quantitative noninvasive assessment of cardiac, arterial, and pulmonary macrophages using the nanotracer Cu-Macrin-a 20-nm spherical dextran nanoparticle assembled from nontoxic polyglucose.

Results: PET imaging using Cu-Macrin faithfully reported accumulation of macrophages in the heart and lung of mice with myocardial infarction, sepsis, or pneumonia. Flow cytometry and confocal microscopy detected the near-infrared fluorescent version of the nanoparticle (Macrin) primarily in tissue macrophages. In 5-day-old mice, Cu-Macrin PET imaging quantified physiologically more numerous cardiac macrophages. Upon intravenous administration of Cu-Macrin in rabbits and pigs, we detected heightened macrophage numbers in the infarcted myocardium, inflamed lung regions, and atherosclerotic plaques using a clinical PET/magnetic resonance imaging scanner. Toxicity studies in rats and human dosimetry estimates suggest that Cu-Macrin is safe for use in humans.

Conclusions: Taken together, these results indicate Cu-Macrin could serve as a facile PET nanotracer to survey spatiotemporal macrophage dynamics during various physiological and pathological conditions. Cu-Macrin PET imaging could stage inflammatory cardiovascular disease activity, assist disease management, and serve as an imaging biomarker for emerging macrophage-targeted therapeutics.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.010586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583675PMC
October 2020

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

Liver X receptors are required for thymic resilience and T cell output.

J Exp Med 2020 10;217(10)

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

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.
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http://dx.doi.org/10.1084/jem.20200318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537384PMC
October 2020

Modifiable Cardiovascular Risk, Hematopoiesis, and Innate Immunity.

Circ Res 2020 04 23;126(9):1242-1259. Epub 2020 Apr 23.

From the Center for Systems Biology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston (M.J.S., F.K.S., M.N.).

Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating evidence indicates that these risk factors may fuel chronic inflammatory processes that are active in atherosclerosis and lead to myocardial infarction and stroke. In concert with hyperlipidemia, maladaptive immune system activities can contribute to disease progression and increase the probability of adverse events. In this review, we discuss recent insight into how the above modifiable risk factors influence innate immunity. Specifically, we focus on pathways that raise systemic myeloid cell numbers and modulate immune cell phenotypes, reviewing hematopoiesis, leukocyte trafficking, and innate immune cell accumulation in cardiovascular organs. Often, relevant mechanisms that begin with lifestyle choices and lead to cardiovascular events span multiple organ systems, including the central nervous, endocrine, metabolic, hematopoietic, immune and, finally, the cardiovascular system. We argue that deciphering such pathways provides not only support for preventive interventions but also opportunities to develop biomimetic immunomodulatory therapeutics that mitigate cardiovascular inflammation.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185037PMC
April 2020

Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus.

Circulation 2020 Jul 22;142(3):244-258. Epub 2020 Apr 22.

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, Boston (F.F.H., M.J.S., D.R., C.S.A., Y.I., K.N., F.K.S., M.N.).

Background: Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.

Methods: In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.

Results: In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less , a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (). We found enhanced HSPC proliferation and increased myeloid cell production in mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic mice, significantly delaying wound closure. Atherosclerosis was accelerated in mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.

Conclusions: In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375017PMC
July 2020

Probing myeloid cell dynamics in ischaemic heart disease by nanotracer hot-spot imaging.

Nat Nanotechnol 2020 05 20;15(5):398-405. Epub 2020 Apr 20.

BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ischaemic heart disease evokes a complex immune response. However, tools to track the systemic behaviour and dynamics of leukocytes non-invasively in vivo are lacking. Here, we present a multimodal hot-spot imaging approach using an innovative high-density lipoprotein-derived nanotracer with a perfluoro-crown ether payload (F-HDL) to allow myeloid cell tracking by F magnetic resonance imaging. The F-HDL nanotracer can additionally be labelled with zirconium-89 and fluorophores to detect myeloid cells by in vivo positron emission tomography imaging and optical modalities, respectively. Using our nanotracer in atherosclerotic mice with myocardial infarction, we observed rapid myeloid cell egress from the spleen and bone marrow by in vivo F-HDL magnetic resonance imaging. Concurrently, using ex vivo techniques, we showed that circulating pro-inflammatory myeloid cells accumulated in atherosclerotic plaques and at the myocardial infarct site. Our multimodality imaging approach is a valuable addition to the immunology toolbox, enabling the study of complex myeloid cell behaviour dynamically.
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http://dx.doi.org/10.1038/s41565-020-0642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416336PMC
May 2020

Hematopoiesis and Cardiovascular Disease.

Circ Res 2020 04 9;126(8):1061-1085. Epub 2020 Apr 9.

From the Center for Systems Biology (W.C.P., M.N., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston.

A central feature of atherosclerosis, the most prevalent chronic vascular disease and root cause of myocardial infarction and stroke, is leukocyte accumulation in the arterial wall. These crucial immune cells are produced in specialized niches in the bone marrow, where a complex cell network orchestrates their production and release. A growing body of clinical studies has documented a correlation between leukocyte numbers and cardiovascular disease risk. Understanding how leukocytes are produced and how they contribute to atherosclerosis and its complications is, therefore, critical to understanding and treating the disease. In this review, we focus on the key cells and products that regulate hematopoiesis under homeostatic conditions, during atherosclerosis and after myocardial infarction.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153537PMC
April 2020

A durable murine model of spleen transplantation with arterial and venous anastomoses.

Sci Rep 2020 03 4;10(1):3979. Epub 2020 Mar 4.

Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada.

The spleen is a large lymphoid organ located in the abdomen that filters blood and regulates the immune system. The extent of mobilization of splenic immune cells to peripheral tissues in health and disease, however, remains poorly understood. This is due, in large part, to a lack of in vivo, spleen-specific lineage tagging strategies. Here, we describe a detailed practical protocol of spleen transplantation and its evaluation for long-term graft survival. Unlike implantation of splenic morsels in the great omentum, our approach uses arterial and venous anastomoses which rapidly restores blood flow and facilitates long-term survival of the graft. The use of congenic mouse strains permits the use of immunofluorescence and flow cytometry-based methodologies to unambiguously track the migration of spleen-derived cells to peripheral tissues.
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http://dx.doi.org/10.1038/s41598-020-60983-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055260PMC
March 2020

Diminished Reactive Hematopoiesis and Cardiac Inflammation in a Mouse Model of Recurrent Myocardial Infarction.

J Am Coll Cardiol 2020 03;75(8):901-915

Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany. Electronic address:

Background: Recurrent myocardial infarction (MI) is common in patients with coronary artery disease and is associated with high mortality. Long-term reprogramming of myeloid progenitors occurs in response to inflammatory stimuli and alters the organism's response to secondary inflammatory challenges.

Objectives: This study examined the effect of recurrent MI on bone marrow response and cardiac inflammation.

Methods: The investigators developed a surgical mouse model in which 2 subsequent MIs affected different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex artery followed by the left anterior descending coronary artery branch. The study characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac magnetic resonance imaging.

Results: A first MI-induced bone marrow "memory" via a circulating signal, reducing hematopoietic maintenance factor expression in bone marrow macrophages. This dampened the organism's reaction to subsequent events. Despite a similar extent of injury according to troponin levels, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. The increase of white blood count in 28 patients was lower after recurrent MI compared with their first MI.

Conclusions: The data suggested that hematopoietic and innate immune responses are shaped by a preceding MI.
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http://dx.doi.org/10.1016/j.jacc.2019.12.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254576PMC
March 2020

The Myocardium: More Than Myocytes.

J Am Coll Cardiol 2019 12;74(25):3136-3138

Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1016/j.jacc.2019.10.031DOI Listing
December 2019

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

Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species.

Sci Transl Med 2019 08;11(506)

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.
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http://dx.doi.org/10.1126/scitranslmed.aaw7736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328283PMC
August 2019

Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload-Induced Cardiac Dysfunction.

Circulation 2019 08 7;140(6):487-499. Epub 2019 Jun 7.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville (Y. Wang, S.S., M.S., Y.Y., C.J., K.W.).

Background: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention.

Methods: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction.

Results: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice.

Conclusions: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684855PMC
August 2019

Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation.

Circulation 2019 07 3;140(3):225-239. Epub 2019 Jun 3.

Vascular Biology and Therapeutics Program (C.M.R., X.Z., N.R., B.A., J.R.K., V.U., Y.S., W.C.S., C.F.-H.), Yale University School of Medicine, New Haven, CT.

Background: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear.

Methods: Triple-knockout mouse lacking expression of eNOS, Cav1, and Ldlr were generated to explore the role of NO production in Cav1-dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy.

Results: We found that absence of Cav1 significantly suppressed atherogenesis in LdlreNOS mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flow-dependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice.

Conclusions: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778687PMC
July 2019

c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells.

Cell Rep 2019 05;27(8):2304-2312.e6

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada. Electronic address:

Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease.
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http://dx.doi.org/10.1016/j.celrep.2019.04.090DOI Listing
May 2019

Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2019 07 16;39(7):1275-1287. Epub 2019 May 16.

Center for Systems Biology (J.E.M., F.K.S.), Massachusetts General Hospital and Harvard Medical School, Boston.

Growth factors, such as CSFs (colony-stimulating factors), EGFs (epidermal growth factors), and FGFs (fibroblast growth factors), are signaling proteins that control a wide range of cellular functions. Although growth factor networks are critical for intercellular communication and tissue homeostasis, their abnormal production or regulation occurs in various pathologies. Clinical strategies that target growth factors or their receptors are used to treat a variety of conditions but have yet to be adopted for cardiovascular disease. In this review, we focus on M-CSF (macrophage-CSF), GM-CSF (granulocyte-M-CSF), IL (interleukin)-3, EGFR (epidermal growth factor receptor), and FGF21 (fibroblast growth factor 21). We first discuss the efficacy of targeting these growth factors in other disease contexts (ie, inflammatory/autoimmune diseases, cancer, or metabolic disorders) and then consider arguments for or against targeting them to treat cardiovascular disease. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/ATVBAHA.119.311994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613384PMC
July 2019

Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates.

Nat Biomed Eng 2018 05 16;2(5):279-292. Epub 2018 Apr 16.

Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4 T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in apolipoprotein E-deficient (Apoe) mice and in non-human primates by in vivo positron-emission tomography imaging. In Apoe mice, a 1-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, which was due to the impaired migration capacity of monocytes, as established by a transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.
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http://dx.doi.org/10.1038/s41551-018-0221-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447057PMC
May 2018

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

Sleep modulates haematopoiesis and protects against atherosclerosis.

Nature 2019 02 13;566(7744):383-387. Epub 2019 Feb 13.

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

Sleep is integral to life. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6C monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.
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http://dx.doi.org/10.1038/s41586-019-0948-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442744PMC
February 2019

Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease.

Nature 2019 02 30;566(7742):115-119. Epub 2019 Jan 30.

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

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways, how our bodies handle nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism. Here we describe a subset of immune cells-integrin β7 natural gut intraepithelial T lymphocytes (natural IELs)-that is dispersed throughout the enterocyte layer of the small intestine and that modulates systemic metabolism. Integrin β7 mice that lack natural IELs are metabolically hyperactive and, when fed a high-fat and high-sugar diet, are resistant to obesity, hypercholesterolaemia, hypertension, diabetes and atherosclerosis. Furthermore, we show that protection from cardiovascular disease in the absence of natural IELs depends on the enteroendocrine-derived incretin GLP-1, which is normally controlled by IELs through expression of the GLP-1 receptor. In this metabolic control system, IELs modulate enteroendocrine activity by acting as gatekeepers that limit the bioavailability of GLP-1. Although the function of IELs may prove advantageous when food is scarce, present-day overabundance of diets high in fat and sugar renders this metabolic checkpoint detrimental to health.
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http://dx.doi.org/10.1038/s41586-018-0849-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367023PMC
February 2019

Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis.

Eur Heart J 2019 08;40(30):2482-2491

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, USA.

Aims: Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1β neutralization in patients post-myocardial infarction with residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1α rather than IL-1β in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice. To shed light on these disparate results, this study investigated the effect of neutralizing IL-1α or/and IL-1β isoforms starting either early in atherogenesis or later in ApoE-/- mice with established atheroma.

Methods And Results: The neutralization of IL-1α or of both IL-1 isoforms impaired outward remodelling during early atherogenesis as assessed by micro-computed tomographic and histologic assessment. In contrast, the neutralization of IL-1β did not impair outward remodelling either during early atherogenesis or in mice with established lesions. Interleukin-1β inhibition promoted a slant of blood monocytes towards a less inflammatory state during atherogenesis, reduced the size of established atheromata, and increased plasma levels of IL-10 without limiting outward remodelling of brachiocephalic arteries.

Conclusion: This study established a pivotal role for IL-1α in the remodelling of arteries during early experimental atherogenesis, whereas IL-1β drives inflammation during atherogenesis and the evolution of advanced atheroma in mice.
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http://dx.doi.org/10.1093/eurheartj/ehz008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685323PMC
August 2019