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Courties, Gabriel

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Courties

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Courties, Gabriel
Author's Publications: search.filters.isAuthorOfPublication.4921d141-01c3-482b-b181-66532883ce21

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Now showing 1 - 7 of 7
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    Chronic variable stress activates hematopoietic stem cells
    (2014) Heidt, Timo; Sager, Hendrik B; Courties, Gabriel; Dutta, Partha; Iwamoto, Yoshiko; Zaltsman, Alex; von zur Muhlen, Constantin; Bode, Christoph; Fricchione, Gregory; Denninger, John; Lin, Charles; Vinegoni, Claudio; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis1,2. While incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known crosstalk 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 reflex3,4. It remains unknown however if chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive 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. Sympathetic nerve fibers release surplus noradrenaline, which uses the β3 adrenergic receptor to signal bone marrow niche cells to decrease CXCL12 levels. Consequently, elevated hematopoietic stem cell proliferation increases output of neutrophils and inflammatory monocytes. When atherosclerosis–prone ApoE−/− mice encounter chronic stress, accelerated hematopoiesis promotes plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.
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    Macrophages retain hematopoietic stem cells in the spleen via VCAM-1
    (The Rockefeller University Press, 2015) Dutta, Partha; Hoyer, Friedrich; Grigoryeva, Lubov S.; Sager, Hendrik B.; Leuschner, Florian; Courties, Gabriel; Borodovsky, Anna; Novobrantseva, Tatiana; Ruda, Vera M.; Fitzgerald, Kevin; Iwamoto, Yoshiko; Wojtkiewicz, Gregory; Sun, Yuan; Da Silva, Nicolas; Libby, Peter; Anderson, Daniel; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    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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    Myocardial Infarction Activates CCR2+ Hematopoietic Stem and Progenitor Cells
    (Elsevier BV, 2015) Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R.; Nahrendorf, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin Robert; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott W.; Scadden, David; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    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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    Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction
    (Ovid Technologies (Wolters Kluwer Health), 2015) Sager, Hendrik B.; Heidt, Timo; Hulsmans, Maarten; Dutta, Partha; Courties, Gabriel; Sebas, Matthew; Wojtkiewicz, Gregory R.; Tricot, Benoit; Iwamoto, Yoshiko; Sun, Yuan; Weissleder, Ralph; Libby, Peter; Swirski, Filip; Nahrendorf, Matthias
    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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    Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease
    (Nature Publishing Group, 2017) Keliher, Edmund J.; Ye, Yu-Xiang; Wojtkiewicz, Gregory R.; Aguirre, Aaron; Tricot, Benoit; Senders, Max L.; Groenen, Hannah; Fay, Francois; Perez-Medina, Carlos; Calcagno, Claudia; Carlucci, Giuseppe; Reiner, Thomas; Sun, Yuan; Courties, Gabriel; Iwamoto, Yoshiko; Kim, Hye-Yeong; Wang, Cuihua; Chen, John; Swirski, Filip; Wey, Hsiao-Ying; Hooker, Jacob; Fayad, Zahi A.; Mulder, Willem J. M.; Weissleder, Ralph; Nahrendorf, Matthias
    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 18F-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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    Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure
    (Ovid Technologies (Wolters Kluwer Health), 2016) Sager, Hendrik B.; Hulsmans, Maarten; Lavine, Kory J.; Moreira, Marina B.; Heidt, Timo; Courties, Gabriel; Sun, Yuan; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F.; Dahlman, James E.; Borodovsky, Anna; Fitzgerald, Kevin; Anderson, Daniel; Weissleder, Ralph; Libby, Peter; Swirski, Filip; Nahrendorf, Matthias
    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 Ly6Chigh 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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    Myocardial Infarction Accelerates Atherosclerosis
    (Nature Publishing Group, 2012) Leuschner, Florian; Robbins, Clinton; Iwamoto, Yoshiko; Thompson, Brian; Carlson, Alicia L.; Heidt, Timo; 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; Katus, Hugo A.; Murphy, Sabina A.; Pittet, Mikael; Lin, Charles; Dutta, Partha; Courties, Gabriel; Wei, Ying; Gorbatov, Rostic; Majmudar, Maulik; Stone, James; Morrow, David; Sabatine, Marc; Vinegoni, Claudio; Moskowitz, Michael; Libby, Peter; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaque in the arterial wall and cause its 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 ischemic 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. When seeking the source of surplus monocytes in plaque, we found that myocardial infarction liberated hematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signaling. 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.