scholarly journals An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

2022 ◽  
Author(s):  
Christoph Kessel ◽  
Isabelle Kone-Paut ◽  
Stephanie Tellier ◽  
Alexandre Belot ◽  
Katja Masjosthusmann ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Cell Activation ◽  
Interleukin 1 ◽  
Endothelial Activation ◽  
Endothelial Cell Activation ◽  
Open Label ◽  
Activation Markers ◽  
Over Expression ◽  
Blood Neutrophils ◽  
Tight Association

Abstract Purpose A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki Disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. Methods Patients’ and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker (n=22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. Results Inflammation in IVIG-resistant KD (n=16) is hallmarked by over-expression of innate immune mediators (particularly IL-6>CXCL10>S100A12>IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n=13) and MIS-C (n=4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release. Conclusion Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modelling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

ENDOTHELIAL CELL ACTIVATION AND HIGH INTERLEUKIN-1 SECRETION IN THE PATHOGENESIS OF ACUTE KAWASAKI DISEASE

The Lancet ◽  
1989 ◽  
Vol 334 (8675) ◽  
pp. 1298-1302 ◽  
Author(s):  
DonaldY.M. Leung ◽  
Evelyn Kurt-Jones ◽  
JaneW. Newburger ◽  
RamziS. Cotran ◽  
JaneC. Burns ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Kawasaki Disease ◽  
Cell Activation ◽  
Interleukin 1 ◽  
Endothelial Cell Activation ◽  
Acute Kawasaki Disease

scholarly journals The Effect of Sex-Mismatched Red Blood Cell Transfusion on Endothelial Cell Activation in Critically Ill Patients

2021 ◽  
pp. 1-8
Author(s):  
Abdulrahman Alshalani ◽  
Lisa van Manen ◽  
Margit Boshuizen ◽  
Robin van Bruggen ◽  
Jason P. Acker ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Blood Cell ◽  
Critically Ill ◽  
Red Blood Cell ◽  
Critically Ill Patients ◽  
Cell Activation ◽  
Endothelial Activation ◽  
Endothelial Cell Activation ◽  
Activation Markers ◽  
Matched Group

<b><i>Background:</i></b> Observational studies suggest that sex-mismatched transfusion is associated with increased mortality. Mechanisms driving mortality are not known but may include endothelial activation. The aim of this study is to investigate the effects of sex-mismatched red blood cell (RBC) transfusions on endothelial cell activation markers in critically ill patients. <b><i>Study Design and Methods:</i></b> In patients admitted to the intensive care unit who received a single RBC unit, blood samples were drawn before (T<sub>0</sub>), 1 h after (T<sub>1</sub>), and 24 h after transfusion (T<sub>24</sub>) for analysis of soluble syndecan-1, soluble intercellular adhesion molecule-1, soluble thrombomodulin (sTM), von Willebrand factor antigen, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα). Changes in the levels of these factors were compared between sex-matched and sex-mismatched groups. <b><i>Results:</i></b> Of 69 included patients, 32 patients were in the sex-matched and 37 patients were in the sex-mismatched group. Compared to baseline, sex-matched transfusion was associated with significant reduction in sTM level (<i>p</i> value = 0.03). Between-group comparison showed that levels of syndecan-1 and sTM were significantly higher in the sex-mismatched group compared to the sex-matched group at T<sub>24</sub> (<i>p</i> value = 0.04 and 0.01, respectively). Also, TNFα and IL-6 levels showed a statistically marginal significant increase compared to baseline in the sex-mismatched group at T<sub>24</sub> (<i>p</i> value = 0.06 and 0.05, respectively), but not in the sex-matched group. <b><i>Discussion:</i></b> Transfusion of a single sex-mismatched RBC unit was associated with higher syndecan-1 and sTM levels compared to transfusion of sex-matched RBC unit. These findings may suggest that sex-mismatched RBC transfusion is associated with endothelial activation.

scholarly journals The Vascular Endothelium in Patients with Dengue Haemorrhagic Fever

2019 ◽  
Vol 7 (14) ◽  
pp. 2221-2225 ◽  
Author(s):  
Mutiara ◽  
Stephen C. L. Koh ◽  
Adang Bachtiar ◽  
Herman Hariman
Keyword(s):  
Vascular Endothelium ◽  
Cell Activation ◽  
Normal Subjects ◽  
Endothelial Activation ◽  
Dengue Haemorrhagic Fever ◽  
Haemorrhagic Fever ◽  
Endothelial Cell Activation ◽  
Study Results ◽  
Plasma Leakage ◽  
D Dimer

BACKGROUND: Dengue fever is the most serious consequence of mosquito-borne infection worldwide. The pathophysiology of DHF in human is complex, which involve endothelial cell activation and impaired endothelial barrier leading to plasma leakage triggering the activation of the haemostatic system. The increased vascular permeability may lead to hypovolemia, hypotension and shock, which is life-threatening. AIM: The objective of the study was to determine the effects of dengue haemorrhagic fever on the vascular endothelium. METHODS: Fifty patients (males 34, females 16), were recruited, Grade 1 (n = 41), Grade 2 (n = 6), Grade 3 (n = 2) and Grade 4 (n = 1) DHF. Blood sampling was performed at the febrile, defervescence and convalescent phases for the determination of haemoglobin, haematocrit, platelets, prothrombin fragment F1 + 2, Von Willebrand Factor (VWF), vascular endothelial growth factor (VEGF) and D-dimer levels. Fifteen normal subjects were recruited to serve as normal controls. RESULTS: The patients aged between 4 and 54 years old. Grades 1 & 2 DHF showed no significant differences in the parameters studied. However, thrombocytopenia, elevated F1 + 2, VWF, VEGF and D-dimer levels were evident in febrile, defervescence and convalescent phases suggesting endothelial activation and plasma leakage. Pleural effusion was observed only in severe DHF. The three patients with Grades 3 and 4 DHF had similar study results. No mortality was recorded in the study. CONCLUSION: In dengue haemorrhagic fever, the vascular endothelium is activated, causing plasma leakage triggering the activation of the haemostatic system creating a hypercoagulable and enhanced fibrinolytic state evident by marked fibrinolysis.

Abstract 66: The Role of the Viral Nef Protein as a Mediator of HIV-1--Induced Endothelial Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ting Wang
Keyword(s):  
Cardiovascular Disease ◽  
T Cells ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Binding Site ◽  
Cell Activation ◽  
Endothelial Activation ◽  
Endothelial Cell Activation ◽  
Hiv 1

With the prevalence of antiviral therapy in the developed world, many HIV-1-infected people die of diseases other than AIDS. One of the emerging major causes is cardiovascular disease, leading to the prediction that the majority of HIV-1 patients are expected to develop cardiovascular complications. Endothelial dysfunction is thought to be a key event in the development of cardiovascular diseases, particularly atherosclerosis. Assays testing the effect of HIV-1 on endothelial activation shows that direct contact with HIV-1 infected T cells enhance endothelial cell activation to a greater extent than HIV-1 alone, suggesting an intracellular HIV-1 protein is responsible for endothelial activation. The HIV-1 viral protein Nef, which is responsible for T cell activation and maintenance of high viral loads in vivo , has been shown to mediate its own transfer to bystander cells. We demonstrate here for the first time that Nef induces nanotube-like conduits connecting T cells and endothelial cells. We also show that Nef is transferred from T cells to endothelial cells via these nanotubes, and is necessary and sufficient for endothelial cell activation. Moreover, we show that SIV-infected macaques exhibit endothelial Nef expression in coronary arteries. Nef expression in endothelial cells causes endothelial apoptosis, ROS and MCP-1 production. Interestingly, a Nef SH3 binding site mutant abolishes Nef-induced apoptosis and ROS formation and reduces MCP-1 production in endothelial cells, suggesting that the Nef SH3 binding site is critical for Nef effects on endothelial cells. Nef induces apoptosis of endothelial cells through an NADPH oxidase- and ROS-dependent mechanism, while Nef-induced MCP-1 production is NF-kB dependent. Taken together, these data suggest that Nef can mediate its transfer from T cells to endothelial cells through nanotubes to enhance endothelial dysfunction.Thus, Nef is a promising new therapeutic target for reducing the risk for cardiovascular disease in the HIV-1 positive population.

scholarly journals Brucella abortus-Stimulated Platelets Activate Brain Microvascular Endothelial Cells Increasing Cell Transmigration through the Erk1/2 Pathway

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 708
Author(s):  
Ana María Rodríguez ◽  
Aldana Trotta ◽  
Agustina P. Melnyczajko ◽  
M. Cruz Miraglia ◽  
Kwang Sik Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Brucella Abortus ◽  
Cell Activation ◽  
Transendothelial Migration ◽  
Endothelial Activation ◽  
Microvascular Endothelial Cell ◽  
Inflammatory Disorder ◽  
Endothelial Cell Activation ◽  
Microvascular Endothelial

Central nervous system invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. A common feature associated with this pathology is blood–brain barrier (BBB) activation. However, the underlying mechanisms involved with such BBB activation remain unknown. The aim of this work was to investigate the role of Brucella abortus-stimulated platelets on human brain microvascular endothelial cell (HBMEC) activation. Platelets enhanced HBMEC activation in response to B. abortus infection. Furthermore, supernatants from B. abortus-stimulated platelets also activated brain endothelial cells, inducing increased secretion of IL-6, IL-8, CCL-2 as well as ICAM-1 and CD40 upregulation on HBMEC compared with supernatants from unstimulated platelets. Outer membrane protein 19, a B. abortus lipoprotein, recapitulated B. abortus-mediated activation of HBMECs by platelets. In addition, supernatants from B. abortus-activated platelets promoted transendothelial migration of neutrophils and monocytes. Finally, using a pharmacological inhibitor, we demonstrated that the Erk1/2 pathway is involved in the endothelial activation induced by B. abortus-stimulated platelets and also in transendothelial migration of neutrophils. These results describe a mechanism whereby B. abortus-stimulated platelets induce endothelial cell activation, promoting neutrophils and monocytes to traverse the BBB probably contributing to the inflammatory pathology of neurobrucellosis.

Changes in ADAMTS 13 Activity and Von Willebrand Factor Parameters during Acute Dengue Infection.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1492-1492
Author(s):  
Darintr Sosothikul ◽  
Panya Seksarn ◽  
Sureeporn Pongsawaluk ◽  
Jeanne M. Lusher
Keyword(s):  
Von Willebrand Factor ◽  
Cell Activation ◽  
Dengue Infection ◽  
Plasma Concentrations ◽  
Endothelial Activation ◽  
Healthy Children ◽  
Endothelial Cell Activation ◽  
Convalescent Phase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Dengue virus causes febrile illnesses: Dengue Fever (DF) and less frequently a life-threatening illness, Dengue Hemorrhagic Fever (DHF). The pathophysiology of hemostatic defect in dengue infection is thought to relate to the direct effect of virus or cytokines on endothelial activation. To study the state of endothelial activation during dengue infection, we measured plasma levels of von Willebrand factor antigen (vWF:Ag), vWF-collagen binding assay (vWF:CBA), and ADAMTS 13 activity in 42 children (20 with DF and 22 with DHF) during 3 phases of illness: febrile, toxic, and convalescent phase. 38 healthy children comprised as controls. Our data shows that both VWF:Ag and vWF:CBA levels were significantly higher in dengue patients (p ≤ 0.001 in both DF and DHF patients) versus controls. DHF patients had significantly higher of VWF: Ag (p = 0.01, versus DF). ADAMTS 13 activity levels were significantly decreased only in DHF patients during 3 phases of the illness (febrile; mean 78%; p = 0.016, toxic; mean 68%; p<0.001 and convalescent; mean 69%; p<0.001 compared to mean 104% of the controls). Compared to DF patients, DHF patients had significantly lower plasma concentrations of ADAMTS 13 activity during the febrile, toxic and convalescent phase (p = 0.039, p = 0.002 and p =0.003, respectively). Endothelial cell activation is a hallmark of dengue infection especially in DHF patients; indicated by a significant rise in VWF:Ag and vWF:CBA and a reciprocal decline in ADAMTS 13 activity.

scholarly journals Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1040
Author(s):  
Mitra Nair ◽  
Maninder Khosla ◽  
Yoshihiro Otani ◽  
Margaret Yeh ◽  
Flora Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Solid Tumors ◽  
Cell Activation ◽  
Leukocyte Adhesion ◽  
Oncolytic Viruses ◽  
Endothelial Cell Activation ◽  
Microscopy Imaging ◽  
Activation Markers

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including ImlygicTM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.

IL-35 Suppresses Lipopolysaccharide-Induced Endothelial Cell Activation Through Downregulation of MAPK Signaling-Mediated Upregulation of Adhesion Molecule VCAM-1

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3310-3310
Author(s):  
Xiaojin Sha ◽  
Shu Meng ◽  
Xinyuan Li ◽  
Jahaira Lopez Pastrana ◽  
Hong Wang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Conflicts Of Interest ◽  
Vascular Inflammation ◽  
Endothelial Activation ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Endothelial Cell Activation

Abstract Abstract 3310 Our previous reports showed that survival/apoptosis of CD4+CD25+Foxp3+ regulatory T cells (Tregs) modulates vascular inflammation even though the mode of Tregs inhibition was unknown. Interleukin-35 (IL-35), consisting of two subunits Epstein-Barr virus–induced gene 3 (EBI3) and p35, is a novel anti-inflammatory cytokine, which is a member of the interleukin-12 (IL-12) cytokine family. IL-35 is produced by Tregs. It has been shown that IL-35 suppresses chronic inflammatory diseases such as asthma and inflammatory bowel diseases. However, an important question of whether IL-35 can carry out Tregs suppression and inhibit endothelial cell (EC) activation in acute inflammation remained unknown. Here we found that IL-35 significantly inhibits lung neutrophil infiltration into the surrounding areas of bronchioles and alveolar space when induced by intraperitoneal injection of lipopolysaccharide (LPS) in wild type mice and EBI3-deficient mice. Furthermore, cremaster microvasculature study using intravital microscopy showed IL-35 significantly suppresses leukocyte adhesion to the vascular wall as well, suggesting IL-35 inhibition of endothelial activation. Mechanistically, IL-35 inhibited LPS-induced upregulation of adhesion molecules on human aortic endothelial cells, a marker of endothelial activation, including vascular cell adhesion molecule 1 (VCAM-1). IL-35 acted through new IL-35 dimeric receptors gp130 and IL-12Rβ2, and inhibited VCAM-1 promoter transcription in mitogen-activated protein kinase (MAPK)-mediated pathway. These results provide a novel insight on Tregs and IL-35 inhibition of vascular inflammation. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document