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Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 42893

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Special Issue Editors

Dr. Madhumita Chatterjee

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Guest Editor

Dept. of Cardiology and Angiology, Internal Medicine III, University Hospital Tübingen Otfried Müller Str. 10, 72076 Tübingen, Germany
Interests: thrombosis; thrombo-inflammation; free radical biology; platelets; neutrophils; coronary artery disease; anti-platelet drug targets

Dr. Judith Cosemans

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Guest Editor

Associate Professor | Head of the Platelet Research Group Cardiovascular Research Institute Maastricht (CARIM) Biochemistry Department, Maastricht University Universiteitssingel 50, 6229 ER Maastricht, The Netherlands
Interests: thrombus formation; platelet biology; antithrombotic medication

Special Issue Information

Dear Colleagues,

Platelets are commendably versatile cells in circulation that not only perform the vital physiological processes of thrombosis-haemostasis, but actively mount inflammatory response in coordination with immune cells. Thrombosis and inflammation go hand-in-hand, whereby each can potentially act as a causative drive or the consequence. Inflammatory interaction of platelets with vascular (e.g. endothelial, smooth muscle cells) and circulatory cells (e.g. monocytes, neutrophils) sets the scene for cardio/cerebrovascular disease, silently leading to thrombo-ischemic adversities like acute myocardial infarction or acute ischemic stroke. Equipped with an array of TLRs, platelets also act as sentinel cells detecting bacterial or viral entry. However, exaggerated inflammatory response to pathogenic intrusion may turn out to be deleterious, as they disrupt physiological haemostasis, and dispose to pathological thrombosis. Both dysregulated coagulation and thrombotic complications have emerged as decisive factors influencing mortality associated with COVID-19 (SARS-CoV-2). Likewise, platelet functions are intricately affected by other viral (e.g. dengue, influenza, HIV-1), bacterial (e.g. E.coli; S. aureus) parasitic (e.g. malaria) infections and sepsis. Therefore, evaluating the molecular drivers of platelet-immune interaction is essential to overcome critical unforeseen challenges as recently encountered during the COVID-19 pandemic. Moreover, platelets themselves are subject to autoimmune or alloimmune challenges owing to inherited or acquired immune pathologies. These not only affect platelet count and turnover (e.g. ImmuneThrombocytoPenia-ITP) but also their functional attributes resulting in life threatening consequences (e.g. Heparin Induced Thrombocytopenia-HIT).

Considering the perplexity of platelet-immune cell interaction, investigations revealing molecular insights and implementing novel therapeutic strategies tailoring this thrombosis-inflammation interface, are undeniably the need of the hour. Ongoing preclinical and clinical studies are pursuing efficacious drug targets and testing novel therapeutics against atherosclerosis, cardio/cerebrovascular disease, deep vein thrombosis, pulmonary embolism, ITP, HIT-associated thrombosis. This ‘Special Issue’ aims to provide an overview and a translational perspective on the multifaceted aspects of thrombo-inflammation. This will not only reveal prospects to exploit therapeutically but also identify obstacles to be surmounted for thromboprophylaxis.

Scope for the special issue: Reviews, research articles, communications and technical notes on basic, preclinical, clinical studies exploring the pathophysiological role of platelets in immune homeostasis or during bacterial or viral infections; the thrombo-inflammatory attributes of platelets in Cardio/Cerebrovascular disease and in platelet associated inherited or acquired immune disorders.

Dr. Madhumita Chatterjee
Dr. Judith Cosemans
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Platelets
thrombo-inflammation
cardio/cerebrovascular disease
infection
immunity
deep vein thrombosis
pulmonary embolism
ITP
HIT
sepsis
anti-platelet therapy
thromboprophylaxis.

Published Papers (14 papers)

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Research

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23 pages, 7511 KiB

Open AccessArticle

Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling

by Tiago F. Granja, David Köhler, Veronika Leiss, Claudia Eggstein, Bernd Nürnberg, Peter Rosenberger and Sandra Beer-Hammer

Cells 2022, 11(19), 3009; https://doi.org/10.3390/cells11193009 - 27 Sep 2022

Cited by 4 | Viewed by 1641

Abstract

Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybernetic parameters, such as controller, sensor, and effector (VASP phosphorylation, P2Y₁₂, ADORAs and GPIIb/IIIa activity), as well as set points (ADP, adenosine) and interfering control and disturbance variables (ischemia). We demonstrate the impact of the regulated platelet–neutrophil complex (PNC) formation in blood and the resulting damage to the affected inflamed tissue. Taken together, extracellular nucleotide signaling, PNC formation, and tissue damage in IIR can be integrated in a controlled cybernetic circle of platelet function, as introduced through this study. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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15 pages, 4310 KiB

Open AccessFeature PaperArticle

Large-Scale Profiling on lncRNAs in Human Platelets: Correlation with Platelet Reactivity

by Yeying Sun, Rongrong Liu, Xiangwen Xia, Luchuan Xing, Jing Jiang, Weihua Bian, Wendy Zhang, Chunhua Wang and Chunxiang Zhang

Cells 2022, 11(14), 2256; https://doi.org/10.3390/cells11142256 - 21 Jul 2022

Cited by 9 | Viewed by 1646

Abstract

Recently, long noncoding RNAs (lncRNAs) have been key regulators for both mRNAs and proteins in nucleated cells. However, the expression profiles of lncRNAs in non-nucleated cells such as platelets are currently unclear. In this study, we determined the expression profiles of lncRNAs in human platelets. We found that 6109 lncRNAs were expressed in human platelets. Interestingly, 338 lncRNAs were differentially expressed in hyperreactive and hyporeactive platelets. Bioinformatics’ analysis revealed that these aberrantly expressed lncRNAs might be related to platelet activity and other platelet functions. To provide a proof of concept, we measured the expression levels of PARLncRNA-1, a down-regulated lncRNA of hyperreactive platelets, in platelets from 12 patients with acute myocardial infarction and their controls. We found that the lncRNA was also significantly down-regulated in platelets from patients, which was partially reversed by treatment with aspirin a known antiplatelet drug. LncRNAs may represent a novel class of modulators for platelet functions. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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12 pages, 4519 KiB

Open AccessCommunication

Group B Streptococcal Hemolytic Pigment Impairs Platelet Function in a Two-Step Process

by Kristin Jahn, Patience Shumba, Phoenicia Quach, Mathias Müsken, Jan Wesche, Andreas Greinacher, Lakshmi Rajagopal, Sven Hammerschmidt and Nikolai Siemens

Cells 2022, 11(10), 1637; https://doi.org/10.3390/cells11101637 - 13 May 2022

Cited by 1 | Viewed by 2380

Abstract

Group B streptococci (GBS) cause a range of invasive maternal–fetal diseases during pregnancy and post-partum. However, invasive infections in non-pregnant adults are constantly increasing. These include sepsis and streptococcal toxic shock syndrome, which are often complicated by systemic coagulation and thrombocytopenia. GBS express a hyper-hemolytic ornithine rhamnolipid pigment toxin with cytolytic and coagulatory activity. Here, we investigated the effects of GBS pigment on human platelets. Infections of platelets with pigmented GBS resulted initially in platelet activation, followed by necrotic cell death. Thus, this study shows that GBS pigment kills human platelets. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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24 pages, 5474 KiB

Open AccessEditor’s ChoiceArticle

Proteomics and Metabolomics Profiling of Platelets and Plasma Mediators of Thrombo-Inflammation in Gestational Hypertension and Preeclampsia

by Luiz Gustavo N. de Almeida, Daniel Young, Lorraine Chow, Joshua Nicholas, Adrienne Lee, Man-Chiu Poon, Antoine Dufour and Ejaife O. Agbani

Cells 2022, 11(8), 1256; https://doi.org/10.3390/cells11081256 - 07 Apr 2022

Cited by 15 | Viewed by 4168

Abstract

Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk factor for preeclampsia. However, it is unclear what biomarkers distinguish PE from GH. Using a discovery size cohort, we aimed to characterize specific plasma and platelet thrombo-inflammatory drivers indicative of PE and differentiate PE from GH. We performed multiplex immunoassays, platelet and plasma quantitative proteomics and metabolomics of PE patients, comparing with non-pregnant (NP), healthy pregnant controls (PC) and GH participants. The expression pattern of plasma proteins and metabolites in PE/GH platelets was distinct from that of NP and PC. Whilst procoagulation in PC may be fibrinogen driven, inter-alpha-trypsin inhibitors ITIH2 and ITIH3 are likely mediators of thrombo-inflammation in GH and PE, and fibronectin and S100A8/9 may be major procoagulant agonists in PE only. Also enriched in PE were CCL1 and CCL27 plasma cytokines, and the platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42), whose effects on platelets were explored using STRING analysis. Through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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15 pages, 1604 KiB

Open AccessArticle

P2Y₁₂ Inhibition in Murine Myocarditis Results in Reduced Platelet Infiltration and Preserved Ejection Fraction

by Sarah Nasreen Schmidt, Wilfried Reichardt, Beat A. Kaufmann, Carolin Wadle, Dominik von Elverfeldt, Peter Stachon, Ingo Hilgendorf, Dennis Wolf, Timo Heidt, Daniel Duerschmied, Karlheinz Peter, Christoph Bode, Constantin von zur Mühlen and Alexander Maier

Cells 2021, 10(12), 3414; https://doi.org/10.3390/cells10123414 - 04 Dec 2021

Cited by 3 | Viewed by 2566

Abstract

Previous mouse studies have shown the increased presence of platelets in the myocardium during early stages of myocarditis and their selective detection by MRI. Here, we aimed to depict early myocarditis using molecular contrast-enhanced ultrasound of activated platelets, and to evaluate the impact of a P2Y₁₂ receptor platelet inhibition. Experimental autoimmune myocarditis was induced in BALB/c mice by subcutaneous injection of porcine cardiac myosin and complete Freund adjuvant (CFA). Activated platelets were targeted with microbubbles (MB) coupled to a single-chain antibody that binds to the “ligand-induced binding sites” of the GPIIb/IIIa-receptor (=LIBS-MB). Alongside myocarditis induction, a group of mice received a daily dose of 100 g prasugrel for 1 month. Mice injected with myosin and CFA had a significantly deteriorated ejection fraction and histological inflammation on day 28 compared to mice only injected with myosin. Platelets infiltrated the myocardium before reduction in ejection fraction could be detected by echocardiography. No selective binding of the LIBS-MB contrast agent could be detected by either ultrasound or histology. Prasugrel therapy preserved ejection fraction and significantly reduced platelet aggregates in the myocardium compared to mice without prasugrel therapy. Therefore, P2Y₁₂ inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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13 pages, 3471 KiB

Open AccessArticle

Effect of Oxidized LDL on Platelet Shape, Spreading, and Migration Investigated with Deep Learning Platelet Morphometry

by Jan Seifert, Hendrik von Eysmondt, Madhumita Chatterjee, Meinrad Gawaz and Tilman E. Schäffer

Cells 2021, 10(11), 2932; https://doi.org/10.3390/cells10112932 - 28 Oct 2021

Cited by 2 | Viewed by 2204

Abstract

Platelets are functionally versatile blood cells involved in thrombosis, hemostasis, atherosclerosis, and immune response. Platelet interaction with the immediate microenvironment in blood, vasculature, and tissues alters platelet morphology. The quantification of platelet morphodynamics by geometrical parameters (morphometry) can provide important insights into how platelets sense and respond to stimulatory cues in their vicinity. However, the extraction of platelet shapes from phase contrast microscopy images by conventional image processing is difficult. Here, we used a convolutional neural network (CNN) to develop a deep-learning-based approach for the unbiased extraction of information on platelet morphodynamics by phase contrast microscopy. We then investigated the effect of normal and oxidized low-density lipoproteins (LDL, oxLDL) on platelet morphodynamics, spreading, and haptotactic migration. Exposure of platelets to oxLDL led to a decreased spreading area and rate on fibrinogen, accompanied by increased formation of filopodia and impaired formation of lamellipodia. Haptotactic platelet migration was affected by both LDL and oxLDL in terms of decreased migration velocity and reduced directional persistence. Our results demonstrate the use of deep learning in investigating platelet morphodynamics and reveal differential effects of LDL and oxLDL on platelet morphology and platelet–matrix interaction. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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12 pages, 787 KiB

Open AccessArticle

Platelet Distribution Width Is Associated with P-Selectin Dependent Platelet Function: Results from the Moli-Family Cohort Study

by Benedetta Izzi, Alessandro Gialluisi, Francesco Gianfagna, Sabatino Orlandi, Amalia De Curtis, Sara Magnacca, Simona Costanzo, Augusto Di Castelnuovo, Maria Benedetta Donati, Giovanni de Gaetano, Marc F. Hoylaerts, Chiara Cerletti, Licia Iacoviello and on behalf of the Moli-family Study Investigators

Cells 2021, 10(10), 2737; https://doi.org/10.3390/cells10102737 - 13 Oct 2021

Cited by 17 | Viewed by 2492

Abstract

Defined as an index of platelet size heterogeneity, the platelet distribution width (PDW) is still a poorly characterized marker of platelet function in (sub)clinical disease. We presently validated PDW as a marker of P-selectin dependent platelet activation in the Moli-family cohort. Platelet-bound P-selectin and platelet/leukocyte mixed aggregates were measured by flow cytometry in freshly collected venous blood, both before and after in vitro platelet activation, and coagulation time was assessed in unstimulated and LPS- or TNFα-stimulated whole blood. Closure Times (CT) were measured in a Platelet Function Analyzer (PFA)-100. Multivariable linear mixed effect regression models (with age, sex and platelet count as fixed and family structure as random effect) revealed PDW to be negatively associated with platelet P-selectin, platelet/leukocyte aggregates and von Willebrand factor (VWF), and positively with PFA-100 CT, and LPS- and TNF-α-stimulated coagulation times. With the exception of VWF, all relationships were sex-independent. In contrast, no association was found between mean platelet volume (MPV) and these variables. PDW seems a simple, useful marker of ex vivo and in vitro P-selectin dependent platelet activation. Investigations of larger cohorts will define the usefulness of PDW as a risk predictor of thrombo-inflammatory conditions where activated platelets play a contributing role. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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14 pages, 2807 KiB

Open AccessFeature PaperArticle

Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions

by Daniëlle M. Coenen, Alexandra C. A. Heinzmann, Silvia Oggero, Hugo J. Albers, Magdolna Nagy, Perrine Hagué, Marijke J. E. Kuijpers, Jean-Marie Vanderwinden, Andries D. van der Meer, Mauro Perretti, Rory R. Koenen and Judith M. E. M. Cosemans

Cells 2021, 10(8), 1998; https://doi.org/10.3390/cells10081998 - 05 Aug 2021

Cited by 6 | Viewed by 3036

Abstract

Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets’ inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s⁻¹. Similar results were obtained with blood from Pde3a deficient mice, indicating that cilostazol effects are mediated via PDE3A. Interestingly, cilostazol specifically reduced the release of phosphatidylserine-positive extracellular vesicles (EVs) from human platelets while not affecting total EV release. Both cilostazol and tadalafil reduced the interaction of human platelets with inflamed endothelium under arterial flow and the release of the chemokines CCL5 and CXCL4 from platelets. Moreover, cilostazol, but not tadalafil, reduced monocyte recruitment and platelet-monocyte interaction in vitro. Conclusions: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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15 pages, 2550 KiB

Open AccessFeature PaperArticle

Interleukin-17A Triggers the Release of Platelet-Derived Factors Driving Vascular Endothelial Cells toward a Pro-Angiogenic State

by Aikaterini Gatsiou, Kateryna Sopova, Alexandros Tselepis and Konstantinos Stellos

Cells 2021, 10(8), 1855; https://doi.org/10.3390/cells10081855 - 22 Jul 2021

Cited by 8 | Viewed by 2367

Abstract

Platelets comprise a highly interactive immune cell subset of the circulatory system traditionally known for their unique haemostatic properties. Although platelets are considered as a vault of growth factors, cytokines and chemokines with pivotal role in vascular regeneration and angiogenesis, the exact mechanisms by which they influence vascular endothelial cells (ECs) function remain underappreciated. In the present study, we examined the role of human IL-17A/IL-17RA axis in platelet-mediated pro-angiogenic responses. We reveal that IL-17A receptor (IL-17RA) mRNA is present in platelets transcriptome and a profound increase is documented on the surface of activated platelets. By quantifying the protein levels of several factors, involved in angiogenesis, we identified that IL-17A/IL17RA axis selectively induces the release of vascular endothelial growth factor, interleukin -2 and -4, as well as monocyte chemoattractant protein -1 from treated platelets. However, IL-17A exerted no effect on the release of IL-10, an anti-inflammatory factor with potentially anti-angiogenic properties, from platelets. Treatment of human endothelial cell two-dimensional tubule networks or three-dimensional spheroid and mouse aortic ring structures with IL-17A-induced platelet releasate evoked pro-angiogenic responses of ECs. Our findings suggest that IL-17A may critically affect platelet release of pro-angiogenic factors driving ECs towards a pro-angiogenic state. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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Review

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30 pages, 993 KiB

Open AccessReview

Extracellular Vesicles as Drivers of Immunoinflammation in Atherothrombosis

by Rosa Suades, Maria Francesca Greco, Teresa Padró and Lina Badimon

Cells 2022, 11(11), 1845; https://doi.org/10.3390/cells11111845 - 05 Jun 2022

Cited by 17 | Viewed by 3353

Abstract

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality all over the world. Extracellular vesicles (EVs), small lipid-bilayer membrane vesicles released by most cellular types, exert pivotal and multifaceted roles in physiology and disease. Emerging evidence emphasizes the importance of EVs in intercellular communication processes with key effects on cell survival, endothelial homeostasis, inflammation, neoangiogenesis, and thrombosis. This review focuses on EVs as effective signaling molecules able to both derail vascular homeostasis and induce vascular dysfunction, inflammation, plaque progression, and thrombus formation as well as drive anti-inflammation, vascular repair, and atheroprotection. We provide a comprehensive and updated summary of the role of EVs in the development or regression of atherosclerotic lesions, highlighting the link between thrombosis and inflammation. Importantly, we also critically describe their potential clinical use as disease biomarkers or therapeutic agents in atherothrombosis. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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20 pages, 2961 KiB

Open AccessReview

Platelet Versus Megakaryocyte: Who Is the Real Bandleader of Thromboinflammation in Sepsis?

by Cédric Garcia, Baptiste Compagnon, Michaël Poëtte, Marie-Pierre Gratacap, François-Xavier Lapébie, Sophie Voisin, Vincent Minville, Bernard Payrastre, Fanny Vardon-Bounes and Agnès Ribes

Cells 2022, 11(9), 1507; https://doi.org/10.3390/cells11091507 - 30 Apr 2022

Cited by 8 | Viewed by 3403

Abstract

Platelets are mainly known for their key role in hemostasis and thrombosis. However, studies over the last two decades have shown their strong implication in mechanisms associated with inflammation, thrombosis, and the immune system in various neoplastic, inflammatory, autoimmune, and infectious diseases. During sepsis, platelets amplify the recruitment and activation of innate immune cells at the site of infection and contribute to the elimination of pathogens. In certain conditions, these mechanisms can lead to thromboinflammation resulting in severe organ dysfunction. Here, we discuss the interactions of platelets with leukocytes, neutrophil extracellular traps (NETs), and endothelial cells during sepsis. The intrinsic properties of platelets that generate an inflammatory signal through the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome are discussed. As an example of immunothrombosis, the implication of platelets in vaccine-induced immune thrombotic thrombocytopenia is documented. Finally, we discuss the role of megakaryocytes (MKs) in thromboinflammation and their adaptive responses. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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21 pages, 17721 KiB

Open AccessReview

Platelets, Bacterial Adhesins and the Pneumococcus

by Kristin Jahn, Thomas P. Kohler, Lena-Sophie Swiatek, Sergej Wiebe and Sven Hammerschmidt

Cells 2022, 11(7), 1121; https://doi.org/10.3390/cells11071121 - 25 Mar 2022

Cited by 10 | Viewed by 3965

Abstract

Systemic infections with pathogenic or facultative pathogenic bacteria are associated with activation and aggregation of platelets leading to thrombocytopenia and activation of the clotting system. Bacterial proteins leading to platelet activation and aggregation have been identified, and while platelet receptors are recognized, induced signal transduction cascades are still often unknown. In addition to proteinaceous adhesins, pathogenic bacteria such as Staphylococcus aureus and Streptococcus pneumoniae also produce toxins such as pneumolysin and alpha-hemolysin. They bind to cellular receptors or form pores, which can result in disturbance of physiological functions of platelets. Here, we discuss the bacteria-platelet interplay in the context of adhesin–receptor interactions and platelet-activating bacterial proteins, with a main emphasis on S. aureus and S. pneumoniae. More importantly, we summarize recent findings of how S. aureus toxins and the pore-forming toxin pneumolysin of S. pneumoniae interfere with platelet function. Finally, the relevance of platelet dysfunction due to killing by toxins and potential treatment interventions protecting platelets against cell death are summarized. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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29 pages, 1966 KiB

Open AccessReview

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

by Madhumita Chatterjee

Cells 2022, 11(2), 213; https://doi.org/10.3390/cells11020213 - 09 Jan 2022

Cited by 5 | Viewed by 4143

Abstract

The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis, i.e., megakaryopoiesis, thrombotic and thrombo-inflammatory actions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coronary syndrome (ACS) patients, and is also associated with improved functional recovery and prognosis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardiac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet-associated cardiovascular disorders, particularly in coronary artery disease (CAD) patients post-MI. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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13 pages, 920 KiB

Open AccessFeature PaperReview

Thrombo-Inflammation: A Focus on NTPDase1/CD39

by Silvana Morello, Elisabetta Caiazzo, Roberta Turiello and Carla Cicala

Cells 2021, 10(9), 2223; https://doi.org/10.3390/cells10092223 - 27 Aug 2021

Cited by 12 | Viewed by 3514

Abstract

There is increasing evidence for a link between inflammation and thrombosis. Following tissue injury, vascular endothelium becomes activated, losing its antithrombotic properties whereas inflammatory mediators build up a prothrombotic environment. Platelets are the first elements to be activated following endothelial damage; they participate in physiological haemostasis, but also in inflammatory and thrombotic events occurring in an injured tissue. While physiological haemostasis develops rapidly to prevent excessive blood loss in the endothelium activated by inflammation, hypoxia or by altered blood flow, thrombosis develops slowly. Activated platelets release the content of their granules, including ATP and ADP released from their dense granules. Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39 dephosphorylates ATP to ADP and to AMP, which in turn, is hydrolysed to adenosine by ecto-5′-nucleotidase (CD73). NTPDase1/CD39 has emerged has an important molecule in the vasculature and on platelet surfaces; it limits thrombotic events and contributes to maintain the antithrombotic properties of endothelium. The aim of the present review is to provide an overview of platelets as cellular elements interfacing haemostasis and inflammation, with a particular focus on the emerging role of NTPDase1/CD39 in controlling both processes. Full article

(This article belongs to the Special Issue Platelets as Pathophysiological Drivers of Thrombo-Inflammation and Immune Response)

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