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  • 1
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    Innate response activator B cells protect against microbial sepsis (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-01-17
    Description: Recognition and clearance of a bacterial infection are a fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279743/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rauch, Philipp J -- Chudnovskiy, Aleksey -- Robbins, Clinton S -- Weber, Georg F -- Etzrodt, Martin -- Hilgendorf, Ingo -- Tiglao, Elizabeth -- Figueiredo, Jose-Luiz -- Iwamoto, Yoshiko -- Theurl, Igor -- Gorbatov, Rostic -- Waring, Michael T -- Chicoine, Adam T -- Mouded, Majd -- Pittet, Mikael J -- Nahrendorf, Matthias -- Weissleder, Ralph -- Swirski, Filip K -- 1R01HL095612/HL/NHLBI NIH HHS/ -- P01-A154904/PHS HHS/ -- P50 CA086355/CA/NCI NIH HHS/ -- P50 CA086355-11/CA/NCI NIH HHS/ -- P50 CA86355/CA/NCI NIH HHS/ -- R01 HL095612/HL/NHLBI NIH HHS/ -- R01 HL095612-03/HL/NHLBI NIH HHS/ -- R24 CA69246/CA/NCI NIH HHS/ -- S10 RR026360/RR/NCRR NIH HHS/ -- U01 HL080731/HL/NHLBI NIH HHS/ -- U01 HL080731-04/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2012 Feb 3;335(6068):597-601. doi: 10.1126/science.1215173. Epub 2012 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22245738" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocyte Subsets/*immunology/metabolism ; Cell Lineage ; Cell Separation ; Escherichia coli Infections/*immunology ; Female ; Flow Cytometry ; Granulocyte-Macrophage Colony-Stimulating Factor/immunology/*metabolism ; *Immunity, Innate ; Immunoglobulin M/metabolism ; Immunophenotyping ; Integrin alpha4beta1/immunology/metabolism ; Lipopolysaccharides ; Lymphocyte Activation ; Lymphocyte Function-Associated Antigen-1/immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Parabiosis ; Peritonitis/*immunology ; Sepsis/*immunology ; Shock, Septic/immunology ; Spleen/immunology ; Toll-Like Receptor 4/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Myocardial infarction accelerates atherosclerosis (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-07-06
    Description: During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dutta, Partha -- Courties, Gabriel -- Wei, Ying -- Leuschner, Florian -- Gorbatov, Rostic -- Robbins, Clinton S -- Iwamoto, Yoshiko -- Thompson, Brian -- Carlson, Alicia L -- Heidt, Timo -- Majmudar, Maulik D -- Lasitschka, Felix -- Etzrodt, Martin -- Waterman, Peter -- Waring, Michael T -- Chicoine, Adam T -- van der Laan, Anja M -- Niessen, Hans W M -- Piek, Jan J -- Rubin, Barry B -- Butany, Jagdish -- Stone, James R -- Katus, Hugo A -- Murphy, Sabina A -- Morrow, David A -- Sabatine, Marc S -- Vinegoni, Claudio -- Moskowitz, Michael A -- Pittet, Mikael J -- Libby, Peter -- Lin, Charles P -- Swirski, Filip K -- Weissleder, Ralph -- Nahrendorf, Matthias -- P50-CA086355/CA/NCI NIH HHS/ -- R01 AI084880/AI/NIAID NIH HHS/ -- R01 EB006432/EB/NIBIB NIH HHS/ -- R01 HL095612/HL/NHLBI NIH HHS/ -- R01 HL095629/HL/NHLBI NIH HHS/ -- R01 HL096576/HL/NHLBI NIH HHS/ -- R01-EB006432/EB/NIBIB NIH HHS/ -- R01-HL095629/HL/NHLBI NIH HHS/ -- R01-HL096576/HL/NHLBI NIH HHS/ -- T32 CA079443/CA/NCI NIH HHS/ -- T32-CA79443/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 19;487(7407):325-9. doi: 10.1038/nature11260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*etiology/*pathology ; Hematopoietic Stem Cells/cytology ; Inflammation/complications ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology ; Myocardial Infarction/*complications/*pathology ; Spleen/cytology ; Stem Cells/cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice [Heart Failure] (2013)
    American Heart Association (AHA)
    Details
    Publication Date: 2013-05-21
    Description: Background— Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6C high monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E–deficient (apoE –/– ) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset–targeted RNAi altered infarct inflammation and healing. Methods and Results— Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE –/– mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18–labeled positron emission tomography agent ( 18 F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P 〈0.05), whereas 18 F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% ( P 〈0.05). Conclusion— CCR2-targeted RNAi reduced recruitment of Ly-6C high monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.
    Keywords: Heart failure - basic studies, Imaging, CT and MRI, Nuclear cardiology and PET
    Electronic ISSN: 1524-4539
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 4
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    Silencing of CCR2 in myocarditis (2015)
    Oxford University Press
    Details
    Publication Date: 2015-06-15
    Description: 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.
    Print ISSN: 0195-668X
    Electronic ISSN: 1522-9645
    Topics: Medicine
    Published by Oxford University Press
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  • 5
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    Endoscopic Time-Lapse Imaging of Immune Cells in Infarcted Mouse Hearts [New Methods in Cardiovascular Biology] (2013)
    American Heart Association (AHA)
    Details
    Publication Date: 2013-03-15
    Description: Rationale: High-resolution imaging of the heart in vivo is challenging owing to the difficulty in accessing the heart and the tissue motion caused by the heartbeat. Objective: Here, we describe a suction-assisted endoscope for visualizing fluorescently labeled cells and vessels in the beating heart tissue through a small incision made in the intercostal space. Methods and Results: A suction tube with a diameter of 2 to 3 mm stabilizes the local tissue motion safely and effectively at a suction pressure of 50 mm Hg. Using a minimally invasive endoscope integrated into a confocal microscope, we performed fluorescence cellular imaging in both normal and diseased hearts in live mice for an hour per session repeatedly over a few weeks. Real-time imaging revealed the surprisingly rapid infiltration of CX 3 CR1 + monocytes into the injured site within several minutes after acute myocardial infarction. Conclusions: The time-lapse analysis of flowing and rolling (patrolling) monocytes in the heart and the peripheral circulation provides evidence that the massively recruited monocytes come first from the vascular reservoir and later from the spleen. The imaging method requires minimal surgical preparation and can be implemented into standard intravital microscopes. Our results demonstrate the applicability of our imaging method for a wide range of cardiovascular research.
    Keywords: Cardiovascular imaging agents/Techniques, Animal models of human disease, Imaging, Ischemic biology - basic studies
    Print ISSN: 0009-7330
    Electronic ISSN: 1524-4571
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 6
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    Origins of tumor-associated macrophages and neutrophils [Immunology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-15
    Description: Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b+ Ly-6Chi monocytic and CD11b+ Ly-6Ghi granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Painting blood vessels with an adhesive drug depot [Engineering] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-12-27
    Description: The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    In Vivo Imaging of MOMP at Single-Cell Resolution (2012)
    The American Association for Cancer Research (AACR)
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    Publication Date: 2012-06-16
    Description: Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment. Cancer Res; 72(12); 2949–56. ©2012 AACR.
    Print ISSN: 0008-5472
    Electronic ISSN: 1538-7445
    Topics: Medicine
    Published by The American Association for Cancer Research (AACR)
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  • 9
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    Implantable hematopoietic microenvironments [Applied Biological Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-11-28
    Description: The environments that harbor hematopoietic stem and progenitor cells are critical to explore for a better understanding of hematopoiesis during health and disease. These compartments often are inaccessible for controlled and rapid experimentation, thus limiting studies to the evaluation of conventional cell culture and transgenic animal models. Here we describe...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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