IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsets

2017 ◽  
Vol 117 (07) ◽  
pp. 1379-1390 ◽  
Author(s):  
Stefan Stojkovic ◽  
Åsa Thulin ◽  
Lena Hell ◽  
Barbara Thaler ◽  
Sabine Rauscher ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Tissue Factor ◽  
Inflammatory Diseases ◽  
Human Monocyte ◽  
Receptor Expression ◽  
Human Monocytes ◽  
Monocyte Subsets ◽  
Prothrombotic State ◽  
St2 Receptor ◽  
Classical Monocytes

SummaryMonocytes and monocyte-derived microvesicles (MVs) are the main source of circulating tissue factor (TF). Increased monocyte TF expression and increased circulating levels of procoagulant MVs contribute to the formation of a prothrombotic state in patients with cardiovascular disease. Interleukin (IL)-33 is a pro-inflammatory cytokine involved in atherosclerosis and other inflammatory diseases, but its role in regulating thrombosis is still unclear. The aim of the present study was to investigate the effects of IL-33 on the procoagulant properties of human monocytes and monocyte-derived MVs. IL-33 induced a time- and concentration-dependent increase of monocyte TF mRNA and protein levels via binding to the ST2-receptor and activation of the NFκB-pathway. The IL-33 treated monocytes also released CD14+TF+ MVs and IL-33 was found to increase the TF activity of both the isolated monocytes and monocyte-derived MVs. The monocytes were classified into subsets according to their CD14 and CD16 expression. Intermediate monocytes (IM) showed the highest ST2 receptor expression, followed by non-classical monocytes (NCM), and classical monocytes (CM). IL-33 induced a significant increase of TF only in the IM (p<0.01), with a tendency in NCM (p=0.06), but no increase was observed in CM. Finally, plasma levels of IL–33 were positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy (r=0.480; p=0.032; n=20). We hereby provide novel evidence that the proinflammatory cytokine IL-33 induces differential TF expression and activity in monocyte subsets, as well as the release of procoagulant MVs. In this manner, IL-33 may contribute to the formation of a prothrombotic state characteristic for cardiovascular disease.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

2015 ◽  
Vol 90 (5) ◽  
pp. 2195-2207 ◽  
Author(s):  
Maria Fernanda de Castro-Amarante ◽  
Cynthia A. Pise-Masison ◽  
Katherine McKinnon ◽  
Robyn Washington Parks ◽  
Veronica Galli ◽  
...  
Keyword(s):  
T Cells ◽  
Leukemia Virus ◽  
Receptor Expression ◽  
Monocyte Subsets ◽  
Viral Dna ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus ◽  
Classical Monocytes ◽  
Intermediate Monocytes

ABSTRACTBecause the viral DNA burden correlates with disease development, we investigated the contribution of monocyte subsets (classical, intermediate, and nonclassical monocytes) to the total viral burden in 22 human T cell leukemia virus type 1 (HTLV-1)-infected individuals by assessing their infectivity status, frequency, as well as chemotactic and phagocytic functions. All three monocyte subsets sorted from HTLV-1-infected individuals were positive for viral DNA, and the frequency of classical monocytes was lower in the blood of HTLV-1-infected individuals than in that of uninfected individuals, while the expression levels of the chemokine receptors CCR5, CXCR3, and CX3CR1 in classical monocytes were higher in HTLV-1-infected individuals than uninfected individuals; the percentage of intermediate monocytes and their levels of chemokine receptor expression did not differ between HTLV-1-infected and uninfected individuals. However, the capacity of intermediate monocytes to migrate to CCL5, the ligand for CCR5, was higher, and a higher proportion of nonclassical monocytes expressed CCR1, CXCR3, and CX3CR1. The level of viral DNA in the monocyte subsets correlated with the capacity to migrate to CCL2, CCL5, and CX3CL1 for classical monocytes, with lower levels of phagocytosis for intermediate monocytes, and with the level of viral DNA in CD8+and CD4+T cells for nonclassical monocytes. These data suggest a model whereby HTLV-1 infection augments the number of classical monocytes that migrate to tissues and become infected and the number of infected nonclassical monocytes that transmit virus to CD4+and CD8+T cells. These results, together with prior findings in a macaque model of HTLV-1 infection, support the notion that infection of monocytes by HTLV-1 is likely a requisite for viral persistence in humans.IMPORTANCEMonocytes have been implicated in immune regulation and disease progression in patients with HTLV-1-associated inflammatory diseases. We detected HTLV-1 DNA in all three monocyte subsets and found that infection impacts surface receptor expression, migratory function, and subset frequency. The frequency of nonclassical patrolling monocytes is increased in HTLV-1-infected individuals, and they have increased expression of CCR1, CXCR3, and CX3CR1. The viral DNA level in nonclassical monocytes correlated with the viral DNA level in CD4+and CD8+T cells. Altogether, these data suggest an increased recruitment of classical monocytes to inflammation sites that may result in virus acquisition and, in turn, facilitate virus dissemination and viral persistence. Our findings thus provide new insight into the importance of monocyte infection in viral spread and suggest targeting of monocytes for therapeutic intervention.

scholarly journals Ten Representative Saponins on Tissue Factor Expression in Human Monocytes: Structure–Activity Relationships and Molecular Docking

2020 ◽  
Vol 15 (3) ◽  
pp. 1934578X2091368
Author(s):  
Yongjiang Zeng ◽  
Xuhua He ◽  
Wenwen Jiang ◽  
Junping Kou ◽  
Boyang Yu
Keyword(s):  
Cardiovascular Disease ◽  
Molecular Docking ◽  
Tissue Factor ◽  
Inhibitory Effect ◽  
Coagulation Cascade ◽  
Human Monocytes ◽  
Messenger Ribonucleic Acid ◽  
Structure Activity Relationships ◽  
Protein Levels ◽  
Structure Activity

Saponins have significant bioactivities in treating cardiovascular disease. Whereas there is a lack of in-depth knowledge about how saponins prevent cardiovascular disease. Tissue factor (TF) is the major initiator of the coagulation cascade and plays an important role in hemostasis and thrombosis. However structure–activity relationships (SARs) of saponins inhibiting TF activity have not been discussed in detail at present. To further clarify the relationships between saponins and TF, in this study, 10 representative saponins were selected to study the inhibitory effect on TF procoagulant activity of monocytes by an improved chromogenic substrate method, and the possible SARs were preliminarily analyzed. Furthermore, molecular docking analysis suggested that 4 representative saponins had a good affinity with TF/FVIIa. In addition, a representative saponin, ruscogenin, decreased both messenger ribonucleic acid and protein levels of TF in human monocytes partly due to its downregulation of nuclear factor kappa-light-chain-enhancer of activated B cells and c-Jun N-terminal kinase pathways. In conclusion, this study provides further explanation for the cardiovascular protection of saponins, and the analysis of SARs between inhibiting TF activity and saponins will be helpful to explore the therapeutic TF inhibitors.

scholarly journals Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology

2011 ◽  
Vol 9 (5) ◽  
pp. 1056-1066 ◽  
Author(s):  
E. SHANTSILA ◽  
B. WRIGLEY ◽  
L. TAPP ◽  
S. APOSTOLAKIS ◽  
S. MONTORO-GARCIA ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Human Monocyte ◽  
Monocyte Subsets

Abstract 1: Human Monocyte Diversity in Cardiovascular Disease Revealed by Mass Cytometry

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Anouk A Hamers ◽  
Graham D Thomas ◽  
Cheryl Kim ◽  
Anh T Nguyen ◽  
Chantel McSkimming ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Suppressor Cells ◽  
Human Monocyte ◽  
Significant Heterogeneity ◽  
Monocyte Subsets ◽  
Mass Cytometry ◽  
Healthy Human ◽  
Healthy Humans ◽  
New Information ◽  
Healthy Donors

Background: Monocytes are critical to the initiation and development of atherosclerosis. To date, 3 distinct human monocyte subsets have been identified based primarily on their expression of the surface markers CD14 and CD16. With the emerging knowledge of myeloid-derived suppressor cells and other myeloid subsets, we hypothesized that monocytes are likely more heterogeneous in composition. Therefore, we set out to use the high dimensionality of mass cytometry to accurately identify and define monocyte subsets in blood of healthy humans and their changes in cardiovascular patients. Methods: Heparinized blood from 12 healthy donors and 15 patients with defined cardiovascular disease (CVD) based on angiography and gensini score was obtained and analyzed by CyTOF mass cytometry. We employed the Phenograph algorithm to cluster and identify all healthy monocyte subsets based on their phenotypes using a 40-marker mass cytometry panel. Results: Phenograph identified a total of 15 monocyte clusters in healthy human blood. By performing hierarchical clustering, we were able to group these clusters into 6 larger meta-clusters and found that most of these meta-clusters fall within the CD14 classical monocyte population, illustrating significant heterogeneity among this monocyte population. Cell numbers of one of these monocyte meta-clusters were significantly increased in blood from patients with CVD. We also identified two subsets of nonclassical monocytes in healthy donors. One of these subsets showed higher expression of the integrin CD61 and tetraspanin CD9, pointing to a possible role for this subset in patrolling and platelet activation. Conclusion: Monocytes are highly diverse with the conventional classical subset showing the most diversity. The numbers and frequencies of some of these monocyte subsets are changed in CVD. Studies to identify their functions in CVD should provide new information for the role of monocytes in CVD.

Abstract P786: Effect of Age and Stroke on Purinergic Receptor P2x4 (p2x4r) Expression in Human Monocyte Subsets

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Rajkumar Verma ◽  
Sharon E DiMauro ◽  
Leslie Blumenfeld ◽  
Pranay Srivastava ◽  
Sanjay Mittal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Purinergic Receptor ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Stroke Recovery ◽  
Monocyte Count ◽  
Monocyte Subsets ◽  
Fluorescent Intensity ◽  
Healthy Control ◽  
Classical Monocytes

Backgrounds: An acute ischemic stroke (AIS) triggers rapid infiltration of circulating immune cells in the brain. P2X4R, a receptor for adenosine triphosphate ATP, regulate activation of circulating monocytes after stroke injury. Over-stimulation of P2X4R contributes to ischemic injury. CD14 ++ CD16 – classical, CD14 ++ CD16 + intermediate, and CD14 + CD16 ++ non-classical monocytes are three primary subsets of monocytes. Alterations in activity of circulating monocyte subsets may independently predict pathogenesis of AIS, however, the role of P2X4R in the activation of these monocyte subsets is not known. Methods: Consecutive AIS patients (60-90 years) undergoing endovascular clot retrieval and healthy control subjects both young (18-45 years) and aged (60-90 years) of both sexes were recruited and informed consent obtained. Flow cytometric analysis of whole blood derived monocytes at 0-2 days (acute, n=10), 3-7 days (subacute, n=9), and 65±20 days (chronic, n=7) after stroke onset were compared with healthy subjects (n=9-10/ age group). Results: Both number of total monocyte counts and P2X4R intensity significantly increase with age when compared between healthy young and aged control (P<0.05). Total monocyte count progressively increased during recovery in AIS patient (P<0.05). No. of CD14 ++ CD16 + intermediate monocytes were significantly reduced after stroke ( p <0.05). Both CD14 ++ CD16 + intermediate, and CD14 + CD16 ++ non-classical monocytes showed a significant increased median fluorescent intensity (P<0.01) of P2X4R at subacute and chronic time after AIS. Conclusions: P2X4R expression increases with age and after stroke. Disappearance of the CD14 + CD16 ++ non-classical monocyte subpopulation from circulation during stroke recovery suggests potential migration of these cells to the site of injury, consistent with their potential role in inflammation/phagocytosis. Increased P2X4R expression in intermediate and non-classical monocytes subpopulation suggest its specific role in selective activation of these monocytes subtype. Detailed molecular characterization of P2X4R response in intermediate and non-classical monocyte subpopulations may provide novel insights into P2X4R’s therapeutic potential during AIS.

Truncated and Microparticle Free Soluble Tissue Factor Bound to Peripheral Monocytes Preferentially Activate Factor VII.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2232-2232 ◽  
Author(s):  
Mohammad Khan ◽  
Takashi Hattori ◽  
Stefan Niewiarowski ◽  
L. Henry Edmunds ◽  
Robert W. Colman
Keyword(s):  
Tissue Factor ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Wide Spectrum ◽  
Factor Vii ◽  
Activate Factor ◽  
Healthy Individuals ◽  
Prothrombotic State ◽  
Low Concentrations

Abstract Soluble plasma tissue factor (TF) circulates in picomolar concentrations in healthy individuals and increases in a wide spectrum of diseases. This study tests the hypothesis that both truncated or long length TF antigens in low concentrations combine with monocytes or platelets to convert factor VII (fVII) to fVIIa. Both recombinant truncated TF (rsTF, kDa 33) and long length (47 kDa) plasma TF (pTF), obtained from pericardial wounds of patients having cardiac surgery using cardiopulmonary bypass, were studied in association with blood cells and TF bearing microparticles. Tissue factor was measured by ELISA. RsTF binds to erythrocytes, platelets, mononuclear cells and neutrophils. The rate of fVII conversion with rsTF (1.0 – 103nmoles/L) is fastest with mononuclear cells, less with platelets, minimal with neutrophils and undetectable with erythrocytes. Both unstimulated and stimulated mononuclear cells or platelets in the presence of 3.5 pmoles/L rsTF or pTF convert fVII (10 nmoles/L) to fVIIa, but the amounts of fVIIa produced is greater in mononuclear cells. When leukocytes or platelets are absent, microparticles associated with 3.5 pmoles/L TF antigen, derived from pericardial wound plasma, do not activate fVII. Stimulated mononuclear cells convert nearly all available fVII (10 nmoles/L) to fVIIa with 3.5 pmoles/L pTF. Unstimulated mononuclear cells convert small amounts of fVII with as little as 1 pmole/L rsTF but no VIIa is produced by platelets, neutrophils or erythrocytes under these conditions. At all concentrations (0.001 to 1m moles/L) mononuclear cells more efficiently convert fVII to fVIIa than platelets. This study shows that stimulated mononuclear cells provide the most efficient phospholipid platform for activation of truncated or long length molecules of soluble TF at low concentrations of TF antigen. The results suggest a new mechanism by which soluble TF, which is increased in clinical inflammatory diseases, may lead to a prothrombotic state.

scholarly journals The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

2017 ◽  
Vol 214 (7) ◽  
pp. 1913-1923 ◽  
Author(s):  
Amit A. Patel ◽  
Yan Zhang ◽  
James N. Fullerton ◽  
Lies Boelen ◽  
Anthony Rongvaux ◽  
...  
Keyword(s):  
Steady State ◽  
Inflammatory Responses ◽  
Dynamic Equilibrium ◽  
Human Monocyte ◽  
Monocyte Subsets ◽  
Deuterium Labeling ◽  
Developmental Relationship ◽  
Endotoxemia Model ◽  
Classical Monocytes

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

scholarly journals Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF-α and IL-1β

2010 ◽  
Vol 298 (2) ◽  
pp. H652-H658 ◽  
Author(s):  
Mohammad M. Khan ◽  
Yuchuan Liu ◽  
Munir E. Khan ◽  
Megan L. Gilman ◽  
Sabina T. Khan ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Tissue Factor ◽  
High Molecular Weight ◽  
Inflammatory Diseases ◽  
Human Monocytes ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Tnf Α ◽  
Chemical Inhibitors ◽  
Inflammatory Bowel

Inflammatory bowel disease and arthritis are associated with contact activation that results in cleavage of kininogen to form high molecular weight kininogen (HKa) and bradykinin. We have previously demonstrated that HKa can stimulate inflammatory cytokine and chemokine secretion from human monocytes. We now show that HKa can upregulate tissue factor antigen and procoagulant activity on human monocytes as a function of time (1–4 h) and HKa concentration (75–900 nM). The amino acid sequence responsible to block HKa effects is G440–H455. The HKa receptor macrophage-1 (Mac-1; CD11b18) is the binding site as shown by inhibition by a monoclonal antibody to CD11b/18. Chemical inhibitors of JNK, ERK, and p38 signaling pathways block cell signaling, as does an inhibitor to the transcription factor NF-κB. A combination of monoclonal antibodies to TNF-α and IL-1β but neither alone inhibited the HKa induction of tissue factor. These results suggest that HKa mimics LPS by triggering a paracrine pathway in monocytes that depends on TNF-α and IL-1β. Antibodies to kininogen or peptidomimetics might be a useful and safe therapy in inflammatory diseases or sepsis involving cytokines.

Sign in / Sign up

Export Citation Format

Share Document