P6303Developmental origin of cardiac macrophages in steady state and myocardial infarction

Abstract Background Macrophages are the most abundant immune cells in the myocardial tissue in steady state. The sterile inflammation caused by myocardial infarction triggers a massive immune reaction, which leads to a profound influx of neutrophils and monocytes. In the postacute phase of infarction macrophages play an essential role in reparative processes. Recently, it has become clear that macrophages in the heart have a dual developmental origin from embryonic and bone marrow (BM) hematopoiesis. In this study, we sought to investigate the contribution of embryonic derived macrophages to the cardiac macrophage pool in steady state as well as the acute and chronic phase after ischemia/reperfusion injury. Methods/Results To address the origin of macrophages in steady state we used different models of lineage tracing to determine the developmental origin of cardiac macrophages. Using FLT3-Cre mice and radiation-independent CD45.1/.2 bone marrow chimera, we found that the resident macrophage population in the heart is mainly independent of definitive hematopoiesis (approximately 70–80% of cardiac macrophages). The BM-dependent population on the other hand is replenished by blood-derived monocytes. Further we used the radiation-independent CD45.1/.2 bone marrow chimera to characterize the origin of macrophages at different time points after I/R-injury. In the acute phase after myocardial infarction we observed a profound influx of BM-derived macrophages in the infarct region and also in the remote area. 30 days after I/R-injury the composition of the resident macrophage pool was mainly comprised of BM-independent macrophages, similar to steady state conditions. To address the role of BM-derived macrophages we used CCR2-ko mice, which have low numbers of inflammatory monocytes in peripheral blood. CCR2-ko mice showed reduced macrophage numbers in the acute phase after myocardial infarction. Using positron emission tomography we investigated the influence of CCR2-deficiency on cardiac function after I/R-injury. In comparison to WT mice, CCR2-ko mice showed a significantly increased infarct size. Cardiac remodeling, determined by end-diastolic volume, on the other hand was improved in CCR2-ko mice. The ejection fraction was similar in both groups. Conclusion The cardiac macrophage pool is mainly comprised of BM-independent macrophages. In response to I/R-injury monocyte-derived macrophages transiently enter the myocardium but do not persist in significant numbers over time. The influx of BM-derived macrophages after I/R-injury was reduced using CCR2-ko mice, which led to improved cardiac remodeling. Our findings are of potential importance for understanding the cardiac immune response and for the therapeutic targeting of macrophages in inflammatory conditions. Acknowledgement/Funding German Society of Cardiology, German Centre for Cardiovascular Research, LMU Excellence, SFB 914

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TRANSMITTING BIPARTITE AND MULTIPARTITE CORRELATIONS VIA SPIN CHAINS UNDER PHASE DECOHERENCE

International Journal of Quantum Information ◽

10.1142/s0219749912500736 ◽

2012 ◽

Vol 10 (06) ◽

pp. 1250073

Author(s):

JIAN-FENG AI ◽

JIAN-SONG ZHANG ◽

AI-XI CHEN

Keyword(s):

Steady State ◽

Anisotropy Parameter ◽

Quantum Correlations ◽

Spin Chains ◽

The Other ◽

Bipartite Entanglement ◽

Other Hand ◽

Long Time ◽

Phase Decoherence ◽

The One

We investigate the transfer of bipartite (measured by cocurrence) and multipartite (measured by global discord) quantum correlations though spin chains under phase decoherence. The influence of phase decoherence and anisotropy parameter upon quantum correlations transfer is investigated. On the one hand, in the case of no phase decoherence, there is no steady state quantum correlations between spins. On the other hand, if the phase decoherence is larger than zero, the bipartite quantum correlations can be transferred through a Heisenberg XXX chain for a long time and there is steady state bipartite entanglement. For a Heisenberg XX chain, bipartite entanglement between two spins is destroyed completely after a long time. Multipartite quantum correlations of all spins are more robust than bipartite quantum correlations. Thus, one can store multipartite quantum correlations in spin chains for a long time under phase decoherence.

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Abstract 81: B Lymphocytes Trigger MCP3-Dependent Mobilization of Monocytes and Promote Adverse Ventricular Remodeling After Myocardial Infarction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a81 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Yasmine Zouggari ◽

Hafid Ait-Oufella ◽

Philippe Bonnin ◽

José Vilar ◽

Coralie Guerin ◽

...

Keyword(s):

Myocardial Infarction ◽

Bone Marrow ◽

Inflammatory Response ◽

Cardiac Function ◽

B Cell ◽

B Lymphocytes ◽

Cardiac Remodeling ◽

Ventricular Remodeling ◽

Cell Depletion ◽

B Cell Depletion

Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and persistent infiltration of innate immune cells, such as neutrophils and Ly6Chi monocytes, has been shown to promote adverse cardiac tissue remodeling. However, little is known regarding the role of mature B lymphocytes, which play a crucial role in the activation of the inflammatory response in several immune-mediated diseases. Here, we hypothesized that B lymphocytes might modulate the inflammatory response and affect the immune-dependent adverse cardiac remodeling. In a mouse model of myocardial infarction, cardiac B lymphocytes levels peaked at day 5 after the onset of infarction. Of interest, treatment with a CD20-specific monoclonal antibody decreased circulating and infiltrating B cell numbers (p=0.0008 and p=0.0002 vs control), reduced infarct size and post-ischemic immunoinflammatory response, and improved cardiac function (p=0.02 vs control) assessed by echocardiography. Intriguingly, B cell depletion was associated with an impairment of Ly6Chi monocytes mobilization from bone marrow (p=0.02 vs control), leading to reduced levels of circulating and infiltrating cardiac monocytes. The acute infarction led to transient increase of both MCP-1 and MCP-3 levels. Interestingly, B cell depletion was associated with a significant and selective reduction of MCP-3 (p=0.03 vs control) but did not alter MCP-1 levels (p=0.11). Cultured activated B cells released MCP-3 and treatment with a neutralizing MCP-3 antibody abrogated B lymphocytes-induced migration of cultured monocytes. Finally, transfer of B cell-depleted splenocytes into Rag1 -/- mice improved cardiac function after myocardial infarction compared to the transfer of non-depleted splenocytes (p=0.005). This effect was abrogated after re-supplementation with B lymphocytes isolated from wild-type mice (p=0.0007) but not from MCP-3-deficient animals (p=0.7008). In conclusion, we show that following acute myocardial infarction, B lymphocytes, trigger an MCP-3-dependent mobilization of Ly6Chi monocytes from the bone marrow to the blood, leading to their recruitment into the injured myocardium and to exacerbation of tissue inflammation, thereby promoting adverse cardiac remodeling.

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Abstract MP153: TET2 Regulates Type I Interferon Signaling in the Hematopoietic Response to Myocardial Infarction

Circulation Research ◽

10.1161/res.127.suppl_1.mp153 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Claire Zhang ◽

David M Calcagno ◽

Avinash Toomu ◽

Kenneth M Huang ◽

Zhenxing Fu ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Bone Marrow ◽

Cardiac Remodeling ◽

Type I Interferon ◽

Myeloid Cells ◽

Type I ◽

Type I Ifn ◽

Clonal Hematopoiesis ◽

Hematopoietic Response

Myocardial infarction (MI) elicits a rapid and vigorous reaction from the bone marrow hematopoietic compartment, inducing a massive efflux of myeloid first responders into the bloodstream. These cells traffic to the infarct, where they mediate cardiac remodeling and repair through inflammatory signaling and recruitment of additional immune cells to the injured myocardium. A hyperinflammatory myeloid compartment, as is produced by mutations in epigenetic regulator TET2 associated with clonal hematopoiesis, can thus drive adverse cardiac remodeling after MI and accelerate progression to heart failure. Whether loss of TET2 alters the transcriptional landscape of MI-induced myelopoiesis remains to be investigated in an unbiased fashion. Here, we performed single-cell RNA sequencing of >16,000 bone marrow myeloid cells isolated from wild-type and Tet2 -/- mice after MI to characterize the emergency hematopoietic response in the presence and absence of TET2. Our data capture distinct transitional states of myeloid lineage commitment and maturation, originating from myeloid progenitors and progressing along divergent granulocytic and monocytic differentiation trajectories. Additionally, we delineate a subpopulation of interferon (IFN)-activated myeloid progenitors, monocytes, and neutrophils characterized by the concerted upregulation of various Type I IFN-stimulated genes, and find the fraction of IFN-activated cells, as well as the degree of activation, to be markedly higher in Tet2 -/- mice. We have previously described activation of this pathway after MI in mice, and demonstrated cardioprotective effects of its genetic or pharmacological inhibition. Our findings reveal heightened activation of the antiviral Type I interferon response among bone marrow myeloid cells of Tet2 -/- mice during MI-induced emergency hematopoiesis. This highlights IFN signaling as a potential candidate driver of cardiovascular pathologies (including atherosclerosis, myocardial infarction, and heart failure) associated with TET2-mediated clonal hematopoiesis. Further studies are necessary to investigate whether Tet2 -/- mice exhibit enhanced response to blockade of Type I IFN signaling after MI, and to determine whether myeloid cells of TET2 -mutant humans are similarly activated.

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The Values of β-TG During the Anticoagulant Therapy in Patients with Venous Thrombosis and Myocardial Infarction

10.1055/s-0039-1687620 ◽

1979 ◽

Author(s):

A. Lucic ◽

R. Borota ◽

Z. Radujkov

Keyword(s):

Myocardial Infarction ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Anticoagulant Therapy ◽

The Other ◽

Prothrombin Activity ◽

Normal Concentration ◽

Preliminary Results ◽

Other Hand

In 38 patients with deep venous thrombosis and 52 patients with myocardial infarction who were on long term anticoagulant therapy, the estimations of β-TG have been done by radioimmunoassay using a kit developed by the Radiochemical Centre, Amersham, England. In the group of patients with deep venous thrombosis, the increased values of β-TG /values which were higher than 80 ng/ml /have been established in 47,3% of the cases and among the patients with myocardial infarction, in 73% of the cases. From the total of 56 patients with increased level of β-TG, in 50 patients the level of prothrombin activity was higher than 20%. On the other hand, in patients with normal concentration of β-TG, the level of prothrombin activity was usually lower than 20%. Our preliminary results suggest the possible use of estimation of β-TG as an important supplementary parameter for evaluation of a substantial efficasy of applied anticoagulant therapy.

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Angiopoietin-1 and Osteopontin Expression by CD138+ Myeloma Cells Rather Than VEGF and CD45 Correlates with Bone Marrow Angiogenesis in Multiple Myeloma Patients at the Diagnosis.

Blood ◽

10.1182/blood.v106.11.2501.2501 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2501-2501

Author(s):

Nicola Giuliani ◽

Simona Colla ◽

Francesca Morandi ◽

Sabrina Bonomini ◽

Mirca Lazzaretti ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Linear Trend ◽

The Other ◽

Vegf Mrna ◽

Myeloma Cells ◽

Other Hand ◽

Significant Difference ◽

Angiopoietin 1

Abstract Bone marrow (BM) angiogenesis is increased in Multiple Myeloma (MM) patients and correlates with disease progression and patient survival. Myeloma cells secrete the main endothelial growth factor VEGF. In mouse models VEGF secretion as well as the angiogenic properties of MM cells correlate with the lack of CD45 expression by MM cells. However, recent data indicate that VEGF plasma cell expression is similar between MGUS and MM patients suggesting that other molecules could be involved. In line with this hypothesis we have recently demonstrated that myeloma cells may also produce factors with angiogenic properties as angiopoietin-1 (ANG-1) and osteopontin (OPN) that are involved in myeloma induced angiogenesis in vitro. In order to identify which factors correlate with BM angiogenesis in MM patients, we have investigated in a cohort of 121 newly diagnosed MM patients (stage I–III) the expression of the angiogenic molecules VEGF, ANG-1 and OPN and their correlation with bone marrow (BM) angiogenesis and CD45 expression by MM cells. We found that 90% of CD138+ MM cells tested were positive for VEGF mRNA. On the other hand we found that 50% and 40 % of MM patients were positive for ANG-1 and OPN mRNA respectively. Using the previously published cut off for CD45 expression we found that 61 out of 121 MM patients were positive for CD45 and 60 out of 121 were negative for CD45 expression. Any correlation was not observed between VEGF expression and BM angiogenesis in MM patients (p=0.5), whereas the number of microvessels X field was higher in Ang-1 positive patients in comparison with Ang-1 negative ones (mean±SE: 6.23±0.2 vs. 2.94±0.1, median: 6.21 vs. 2.79; p=0.001,) and the microvascular density (MVD) was significantly increased (32.98±1.7 vs. 14.55±1.3, median: 34.69 vs. 13.04; p<0.01; capillaries: 26.73±1.3 vs. 10.42±0.8, median: 24.06 vs. 9.04; p<0.01, small venules: 9.56 ±0.5 vs. 4.14±0.5, median: 10.60 vs. 3.65; p<0.01). Furthermore a significantly positive correlation between Ang-1 expression and MVD was found (Pearson Chi-square: p=0.036, Cochran’s Linear Trend: p=0.01). A significantly higher MVD was also observed in the group of patients positive for OPN, (mean±SE: 29.1±0.7 vs. 17.55±0.37; p<0.01) and similarly, the number of microvessels per field was higher in OPN positive patients in comparison with OPN negative ones (mean±SE: 6.7±0.15 vs. 4.28±0.04; p=0.05). On the other hand, any significant difference was not observed between CD45 positive and CD45 negative patients for the expression of VEGF (p=0.4), ANG-1 (p=0.3) and OPN (p=0.09). Consistently we did not find any significant difference in both MVD and number of vessels X field between CD45 positive patients as compared with CD45 negative ones (p=0.5 and p=0.4, respectively). Finally, a multivariate analysis confirmed that VEGF and CD45 did not correlate with the BM angiogenesis showing that ANG-1 expression by MM cells was more tightly correlated with MVD and the number of vessels X field as compared to OPN. Our data indicate that ANG-1 and in part OPN rather than VEGF and CD45 expression by MM cells are the critical determinants correlated with the increase of BM angiogenesis that occurs in MM patients at the diagnosis.

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PREANNOUNCED OPTIMAL TAX REFORM

Macroeconomic Dynamics ◽

10.1017/s1365100505040204 ◽

2005 ◽

Vol 9 (2) ◽

pp. 150-169 ◽

Cited By ~ 10

Author(s):

DAVID DOMEIJ ◽

PAUL KLEIN

Keyword(s):

Steady State ◽

Fiscal Policy ◽

Tax Reform ◽

The Other ◽

Welfare Gain ◽

Welfare Gains ◽

Optimal Tax ◽

Other Hand ◽

Optimal Fiscal Policy ◽

Implementation Lag

In constitutional democracies, laws take time to be deliberated upon, to be passed, and to be implemented. Motivated by this observation, we study the properties of optimal tax reform when it has to be announced in advance of its implementation. We find that a delay between announcement and implementation has large effects on the optimal fiscal policy during the transition to the new steady state. On the other hand, we find that the welfare gains from optimal tax reform are fairly robust to the introduction of an implementation lag. Increasing the lag from zero to four years reduces the welfare gains by less than a quarter. Moreover, it turns out that this reduction of the welfare gain is mainly due to the delay itself rather than the effect of preannouncement on the character of the optimal tax reform.

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A note on dynamical compensation and its relation to parameter identifiability

10.1101/123489 ◽

2017 ◽

Cited By ~ 2

Author(s):

Omer Karin ◽

Uri Alon ◽

Eduardo Sontag

Keyword(s):

Experimental Data ◽

Steady State ◽

The Other ◽

Apparent Discrepancy ◽

Parameter Identifiability ◽

Other Hand ◽

The Face ◽

System Variables

AbstractWe recently identified a motif for dynamical compensation (DC) – a property where a system maintains the dynamics and steady-state of a regulated variable robust in the face of fluctuations in key parameters. Such parameters are therefore unidentifiable from measurements of the regulated variable at steady-state. On the other hand, since the models showing dynamical compensation are typically non-redundant, their parameters are identifiable from experimental data. We clarify this apparent discrepancy by requiring that the parameters of DC circuits be identifiable both away from steady-state and when measuring other system variables. We use this observation to provide a definition for DC in terms of parameter identifiability and discuss its relevance for the examples provided in Karin et al.

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Cytokine Gene Polymorphisms in Turkish Patients with Childhood Chronic Myeloid Leukemia.

Blood ◽

10.1182/blood.v106.11.4368.4368 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4368-4368

Author(s):

Kursat Ozdilli ◽

Fatma Oguz ◽

Yeliz Duvarci ◽

Hulya Bilgen ◽

Sema Anak ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

The Other ◽

Fine Tuning ◽

Control Group ◽

Cytokine Gene ◽

Chi Square ◽

Other Hand ◽

Genotype Frequencies

Abstract Cytokines are necessary for normal hematopoiesis in the bone marrow and provide a means of fine-tuning bone marrow function in response to stimulation. Several of cytokines generated during both innate and adaptive immune responses stimulate the growth and differantiation of bone marrow progenitor cells. The vast majority of polymorphism found in cytokine genes and their reseptors are located in non coding regions. Cytokine gene polymorphism may be implicated in the pathogenesis of infections, autoimmun disease and malignancies via their effect on cytokine production and regulation. It is known that leukemic cells proliferate under the influence of cytokines. Our aim is to analyze cytokine gene profiles in patients with chronic myeloid leukemia (CML)in order to clarify the pathogenesis of CML. Genomic DNA from 26 CML patients were analysed. Genotyping was performed by polymerase chain reaction with sequence specific primers (PCR-SSP) using “ One lamda” kit in 26 childhood CML patients 60 unrelated healthy individuals. Genotype frequencies between CML patients and controls were compared using Chi-Square Yates, Fisher’s Exact Tests. In this study; 26 CML patients with a mean age of 15,6±5,3 and 60 healthy controls with a mean age of 18,2±5,4 were investigated. In CML patients the frequencies of TGF-b(TC/GG) genotype (in chi-square p=0,01,odds ratio(OR)=3,46, 95% confidence interval (CI) 1,3–9,04) and IL-10 (GCC/ATA) genotype (in chi-square p=0,04,OR=3,3, 95% CI 0,9–11,1 were found higher in patients with CML compared to the control group. On the other hand IL-6 (CC) genotype (in chi-square p=0,012,OR=0,17, 95% CI 0,4–0,76 frequency was found higher in the control group compared to the patients with CML. As a conclusion higher frequency in TGF-b(TC/GG) and IL-10(GCC/ATA) genotype polymorphism were significantly higher in the patients with CML so it may predispose to CML. On the other hand IL-6 (CC) genotype might be the preventive factor for CML. The present study is rather significant that it is the study which assessed the relation of the cytokines in patients with CML compared to the control group taken from the genetic pool of The Turkish population, we believe studies like this will eventually help to understand the pathogenesis of CML and the role cytokines play in CML,but larger groups of studies must be done in future.

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Overexpression of CTLA-4 in the Bone Marrow of Patients with Multiple Myeloma As a Sign of Local Accumulation of Immunosuppressive Tregs – Perspectives for Novel Treatment Strategies

Blood ◽

10.1182/blood.v118.21.1829.1829 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1829-1829 ◽

Cited By ~ 2

Author(s):

Walter Moises Tobias Braga ◽

Andre Luiz Vettore ◽

Ana Carolina Carvalho ◽

Djordje Atanackovic ◽

Gisele W.B. Colleoni

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Tumor Cells ◽

T Cell Activation ◽

Th17 Cells ◽

Conflicts Of Interest ◽

Treg Cells ◽

Genetic Alterations ◽

The Other ◽

Other Hand

Abstract Abstract 1829 Introduction: Multiple myeloma (MM) development involves a series of genetic alterations and changes in the bone marrow (BM) microenvironment, favoring the growth of the tumor and failure of local immune control. T regulatory (Treg) cells play an important role in the maintenance of self-tolerance and modulation of overall immune responses against infections and tumor cells. T-helper-17 (Th17) cells, on the other hand, have a critical function in eradicating extracellular pathogens and tumor cells. The balance between Treg and Th17 cells may be essential for maintaining homeostasis of anti-tumor immunity. The aim of our study was to characterize the expression of Treg- (FOXP3 and CTLA-4) and Th17-related (RORγt) genes in total MM bone marrow samples to assess the local immune milieu as a potential therapeutic target in this still incurable disease. Material and Methods: Expression of FOXP3, CTLA-4 and RORγt was determined by quantitative real-time PCR (qPCR) in BM aspirates of 55 MM patients, 4 patients with monoclonal gammopathy of undetermined significance (MGUS), and 5 healthy BM donors. Genes were considered overexpressed when their expression was at least two times higher in myeloma BM than in normal samples. Results:RORγt showed a non-significant overexpression in MM patients compared to controls. FOXP3, on the other hand, showed a 3.6-fold higher expression in MM patients compared to controls but the difference was not significant and was overexpressed in 63% of MM cases. CTLA-4 expression was 14.6-fold higher in MM patients compared to controls (p=0.03, Mann-Whitney test) and was overexpressed in 70% of MM cases. Importantly the CTLA-4/RORyt ratio was significantly higher in MM samples compared to controls (p = 0.009) while this difference was not significant when controls were compared to MGUS patients, suggesting that the immunological imbalance worsens with the progression of disease. Conclusions: CTLA-4 (cytotoxic T-lymphocyte antigen-4), an intracellular and membrane inhibitory protein expressed on Treg cells, modulates T-cell activation and is critical in maintaining immune tolerance to self-antigens. Monoclonal antibodies targeting CTLA-4 have improved the survival of patients with metastatic melanoma in clinical trials. The myeloma-related overexperssion of CTLA-4 and the increased CTLA-4/RORyt ratio suggest an accumulation of immunosuppressive Tregs in the tumor microenvironment and/or an immediate involvement of this gene in the development and progression of myeloma. If protein expression confirms gene expression imbalance between Treg and Th17 subpopulations, therapeutic approaches that specifically target CTLA-4-expressing Treg myeloma cases may provide a new treatment strategy for this disease. (Supported by CNPq, Brazil). Disclosures: No relevant conflicts of interest to declare.

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