The Role of Platelets in Atherothrombosis

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Zane S. Kaplan ◽  
Shaun P. Jackson
Keyword(s):  
Endothelial Cells ◽  
Platelet Adhesion ◽  
Inflammatory Diseases ◽  
Central Element ◽  
Biological Response ◽  
Precise Control ◽  
Autoimmune And Inflammatory Diseases ◽  
Adhesive Interactions ◽  
Atherosclerotic Process

Abstract Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.

Pathogenic role of anti-endothelial cell antibodies in autoimmune rheumatic diseases

Lupus ◽  
2009 ◽  
Vol 18 (13) ◽  
pp. 1233-1238 ◽  
Author(s):  
DS Domiciano ◽  
JF Carvalho ◽  
Y. Shoenfeld
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Inflammatory Diseases ◽  
Endothelial Damage ◽  
Systemic Lupus Erythematous ◽  
Pathogenic Role ◽  
Autoimmune Rheumatic Diseases ◽  
Pathological Conditions ◽  
Autoimmune And Inflammatory Diseases

Anti-endothelial cells antibodies have been detected in numerous autoimmune and inflammatory diseases, including systemic lupus erythematous, rheumatoid arthritis, vasculitis and sarcoidosis. Anti-endothelial cells antibodies bind to endothelial cell antigens and induce endothelial damage. Their effects on the endothelial cell have been considered responsible, at least in part, by the vascular injury which occurs in these pathological conditions.

Conversion of platelets from a proaggregatory to a proinflammatory adhesive phenotype: role of PAF in spatially regulating neutrophil adhesion and spreading

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1879-1886 ◽  
Author(s):  
Suhasini Kulkarni ◽  
Kevin J. Woollard ◽  
Stephen Thomas ◽  
David Oxley ◽  
Shaun P. Jackson
Keyword(s):  
Platelet Activation ◽  
Vascular Injury ◽  
Platelet Adhesion ◽  
Inflammatory Diseases ◽  
Platelet Activating Factor ◽  
Annexin A5 ◽  
Neutrophil Adhesion ◽  
Adhesive Interactions ◽  
First Time

Abstract The ability of platelets to provide a highly reactive surface for the recruitment of other platelets and leukocytes to sites of vascular injury is critical for hemostasis, atherothrombosis, and a variety of inflammatory diseases. The mechanisms coordinating platelet-platelet and platelet-leukocyte interactions have been well defined and, in general, it is assumed that increased platelet activation correlates with enhanced reactivity toward other platelets and neutrophils. In the current study, we demonstrate a differential role for platelets in supporting platelet and neutrophil adhesive interactions under flow. We demonstrate that the conversion of spread platelets to microvesiculated procoagulant (annexin A5–positive [annexin A5+ve]) forms reduces platelet-platelet adhesion and leads to a paradoxical increase in neutrophil-platelet interaction. This enhancement in neutrophil adhesion and spreading is partially mediated by the proinflammatory lipid, platelet-activating factor (PAF). PAF production, unlike other neutrophil chemokines (IL-8, GRO-α, NAP-2, IL-1β) is specifically and markedly up-regulated in annexin A5+ve cells. Physiologically, this spatially controlled production of PAF plays an important role in localizing neutrophils on the surface of thrombi. These studies define for the first time a specific proinflammatory function for annexin A5+ve platelets. Moreover, they demonstrate an important role for platelet-derived PAF in spatially regulating neutrophil adhesion under flow.

Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment

2000 ◽  
Vol 100 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Michael J. HICKEY
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Nitric Oxide Synthase ◽  
Cell Types ◽  
Adhesive Interactions ◽  
Oxide Synthase ◽  
Leucocyte Recruitment

Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesion of leucocytes in the microcirculation. However, during various types of inflammation, expression of the inducible form of nitric oxide synthase (iNOS) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in unstimulated tissue. Under these conditions, it is less well understood whether iNOS-derived nitric oxide retains the anti-adhesive capabilities of constitutively produced nitric oxide. This review summarizes work done to examine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endothelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experiments were extended by the advent of the iNOS-deficient (iNOS-/-) mouse. Intravital microscopy studies of these mice have indicated that, under conditions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leucocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other studies have observed either no effect or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Taken together, these studies suggest that the importance of iNOS in modulating leucocyte recruitment can vary according to the type of inflammatory response.

scholarly journals The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Tao Yu ◽  
Young-Su Yi ◽  
Yanyan Yang ◽  
Jueun Oh ◽  
Deok Jeong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Critical Role ◽  
Biological Response ◽  
Antiviral Defense ◽  
Functional Roles ◽  
Virus Interaction

Inflammation is a complex biological response of tissues to harmful stimuli such as pathogens, cell damage, or irritants. Inflammation is considered to be a major cause of most chronic diseases, especially in more than 100 types of inflammatory diseases which include Alzheimer's disease, rheumatoid arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, hepatitis, and Parkinson's disease. Recently, an increasing number of studies have focused on inflammatory diseases. TBK1 is a serine/threonine-protein kinase which regulates antiviral defense, host-virus interaction, and immunity. It is ubiquitously expressed in mouse stomach, colon, thymus, and liver. Interestingly, high levels of active TBK1 have also been found to be associated with inflammatory diseases, indicating that TBK1 is closely related to inflammatory responses. Even though relatively few studies have addressed the functional roles of TBK1 relating to inflammation, this paper discusses some recent findings that support the critical role of TBK1 in inflammatory diseases and underlie the necessity of trials to develop useful remedies or therapeutics that target TBK1 for the treatment of inflammatory diseases.

scholarly journals A Disintegrin and Metalloprotease 15 is Expressed on Rheumatoid Arthritis Synovial Tissue Endothelial Cells and may Mediate Angiogenesis

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 32 ◽  
Author(s):  
Shinichiro Nishimi ◽  
Takeo Isozaki ◽  
Kuninobu Wakabayashi ◽  
Hiroko Takeuchi ◽  
Tsuyoshi Kasama
Keyword(s):  
Rheumatoid Arthritis ◽  
Endothelial Cells ◽  
Conditioned Medium ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Tnf Α ◽  
Adhesion Index

A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.

Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

2016 ◽  
Vol 397 (12) ◽  
pp. 1315-1333 ◽  
Author(s):  
Isabel Meininger ◽  
Daniel Krappmann
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Antigen Receptor ◽  
Lymphocyte Activation ◽  
Downstream Signaling ◽  
Antigen Receptor Signaling ◽  
Autoimmune And Inflammatory Diseases ◽  
And Function

Abstract The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigen-receptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated ‘chronic’ CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

scholarly journals Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stephen Watt ◽  
Louella Vasquez ◽  
Klaudia Walter ◽  
Alice L. Mann ◽  
Kousik Kundu ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Disease Susceptibility ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Genetic Associations ◽  
Functional Interpretation ◽  
Autoimmune And Inflammatory Diseases ◽  
Immune Traits ◽  
Downstream Gene Expression

AbstractNeutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.

scholarly journals Complement C3 Genotype Variants and Risk of Lung Cancer Mortality

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Poul Suadicani ◽  
Hans Ole Hein ◽  
Finn Gyntelberg
Keyword(s):  
Lung Cancer ◽  
Innate Immunity ◽  
Cancer Mortality ◽  
Inflammatory Diseases ◽  
Central Element ◽  
Humoral Response ◽  
Lung Cancer Mortality ◽  
Complement C3

Inflammation and genetic susceptibility influence the risk of lung cancer. During recent years, the role of complement as a part of the humoral response has advanced from being considered complementary to being regarded as a central element in innate immunity. C3 complement allotypes F and S have been associated with a number of inflammatory diseases. The C3F allele frequency is approximately 20% in Caucasian populations and the C3S approximately 80%, resulting in the three predominant genotypes FF (4%), FS (32%), and SS (64%). To our knowledge, no studies have investigated if different C3 allotypes or genotypes predict the risk of lung cancer. We tested in a long-term followup of 3,197 men aged 53 to 74 years the hypothesis that risk of lung cancer would depend on C3 complement genotypes. During 16 years, 160 subjects (5.0%) died from lung cancer, 68 men (6.1%) among complement C3 genotypes FS/FF, and 92 men (4.4%) among genotype SS; age-adjusted hazard ratio with 95%CI (HR) was 1.42 (1.04–1.94) and strongest, 2.71 (1.34–5.45), among the oldest fifth. C3 complement genotype variants were significantly associated with lung cancer mortality.

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