Platelet-platelet and platelet-leukocyte interactions induced by outer membrane vesicles from N. meningitidis

Mirlashari, Mohammad Reza; Hagberg, Inger Anne; Lyberg, Torstein

doi:10.1080/09537100220122448

Cited by 29 publications

(16 citation statements)

References 18 publications

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“…Nevertheless, other laboratories have observed increased platelet aggregation but not P-selectin expression in response to LPS, whereas fragments of Gram-negative bacteria induced both. 16 Although P-selectin is often considered a good marker of platelet activation, clearly our study and others have observed platelet adhesion independent of P-selectin in response to LPS. Our own results support the lack of P-selectin expression in response to LPS, but our results also suggest that LPS can activate the platelet sufficiently to adhere to fibrinogen in vitro.…”

Section: Discussionsupporting

confidence: 52%

“…15 A number of other studies, however, have reported some subtle responses of platelets to certain types of LPS and more avid responses to fragments of Gram-negative bacteria. 16 Clearly, a reassessment of the mechanism of platelet activation in endotoxemia is warranted in light of recent reports that platelets are potentially important in different inflammatory scenarios, including sepsis. 13,17,18 19,20 The beneficial effects of GPIIb/IIIa inhibition could be related to reduced recruitment of activated platelets into lungs and liver, where they could cause tissue damage.…”

Section: Introductionmentioning

confidence: 99%

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Platelets express functional Toll-like receptor-4

Andonegui

Kerfoot

McNagny

et al. 2005

Blood

431

415

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Profound thrombocytopenia occurs in humans with sepsis and in mice administered lipopolysaccharide (LPS). Growing evidence indicates that platelets may contribute to these abnormalities, but whether that is a direct result of LPS activation of platelets or an indirect result of other inflammatory mechanisms remains unclear. Here we demonstrate that although platelets do not increase P-selectin expression in response to LPS, platelets bind more avidly to fibrinogen under flow conditions in a Toll-like receptor-4 (TLR4)-dependent manner. In addition, we find that CD41 ؉ megakaryocytes grown from fetal livers and adult circulating platelets express significant amounts of TLR4. LPS induced thrombocytopenia in wild-type mice but not in TLR4-deficient (TLR4 def ) mice. Wild-type platelets accumulated in the lungs of wild-type mice in response to LPS; TLR4 def platelets did not. However, wild-type platelets did not accumulate in the lungs of LPS-treated TLR4 def mice. Neutrophils also accumulated in the lungs, and this preceded platelet accumulation. Neutrophil depletion completely abolished LPS-induced platelet sequestration into the lungs, but platelet depletion did not affect neutrophil accumulation. Thus, our data show for the first time that platelets do express functional levels of TLR4, which contribute to thrombocytopenia through neutrophil-dependent pulmonary sequestration in response to LPS. ( IntroductionLipopolysaccharide (LPS) or endotoxin is the main structural component of Gram-negative bacteria and an important player in the ability of host cell detection of these foreign pathogens. LPS may also play a fundamental role in sepsis. LPS recognition by mammalian cells occurs through a multiprotein interaction. First, a plasma protein, LPS-binding protein (LBP), binds LPS and transfers LPS monomers to CD14. 1 CD14 is a high-affinity receptor for LPS present both as a soluble form in blood or as a glycophosphoinositol (GPI)-anchored protein on the surfaces of myeloid lineage cells. Indeed, CD14 Ϫ/Ϫ mice are at least 100 times more resistant to LPS-induced death. 2 However, LPS signaling in cells can only occur if the transmembrane molecule TLR4 is activated. TLR4 belongs to the family of Toll-like receptors that are type 1 transmembrane proteins characterized by an extracellular domain containing multiple leucine-rich repeats, a single transmembrane domain, and an intracellular Toll/interleukin-1 (IL-1) receptor (TIR) domain. Stimulation of TLR4 by LPS activates a signaling cascade that is characterized by the production of proinflammatory cytokines and subsequent immune response. The importance of TLR4 in LPS-induced signaling is emphasized by the fact that TLR4 def mice (C57BL/10ScCr), TLR4 knockout mice, and mice with a single point mutation in the TLR4 gene (C3H/HeJ) are resistant to the immunostimulatory and pathophysiologic effects of LPS. [3][4][5] TLR4 is present in many different cell types, including dendritic cells, neutrophils, macrophages, epithelial cells, keratinocytes, and endothelial cells. ...

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Platelets express functional Toll-like receptor-4

Andonegui

Kerfoot

McNagny

et al. 2005

Blood

431

415

View full text Add to dashboard Cite

show abstract

“…More recently, platelets were shown to be directly activated by Haemophilus somnus and its lipo-oligosaccharide (30). Similarly, platelet activation by outer vesicles from Neisseria meningitidis was shown to play an important role in microthrombosis and organ dysfunction observed in patients with meningococcal septicemia (31). The report by different groups that Toll-like receptor 4, a major receptor for bacterial LPS, is expressed in platelets (32,33) further suggests that these cells can detect and respond to infectious agents.…”

Section: Discussionmentioning

confidence: 98%

Exou-Induced Vascular Hyperpermeability and Platelet Activation in the Course of Experimental Pseudomonas Aeruginosa Pneumosepsis

Machado¹,

Assis²,

Leão³

et al. 2010

Shock

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To address the question whether ExoU, a Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, can induce hemostatic abnormalities during the course of pneumosepsis, mice were instilled i.t. with the ExoU-producing PA103 P. aeruginosa or with a mutant obtained by deletion of the exoU gene. Control animals were instilled with sterile vehicle. To assess the role of ExoU in animal survival, mice were evaluated for 72 h. In all the other experiments, animals were studied at 24 h after infection. PA103-infected mice showed significantly higher mortality rate, lower blood leukocyte concentration, and higher platelet concentration and hematocrit than animals infected with the bacterial mutant, as well as evidences of increased vascular permeability and plasma leakage, which were confirmed by our finding of higher protein concentration in bronchoalveolar lavage fluids and by the Evans blue dye assay. Platelets from PA103-infected mice demonstrated features of activation, assessed by the flow cytometric detection of higher percentage of P-selectin expression and of platelet-derived microparticles as well as by the enzyme immunoassay detection of increased thromboxane A2 concentration in animal plasma. Histopathology of lung and kidney sections from PA103-infected mice exhibited evidences of thrombus formation that were not detected in sections of animals from the other groups. Our results demonstrate the ability of ExoU to induce vascular hyperpermeability, platelet activation, and thrombus formation during P. aeruginosa pneumosepsis, and we speculate that this ability may contribute to the reported poor outcome of patients with severe infection by ExoU-producing P. aeruginosa.

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“…Platelets can engulf viruses and bacteria (Youssefian et al 2002) and also aggregate in response to whole bacteria (Boukour and Cramer 2005;Byrne et al 2003;Kalvegren et al 2003;Mirlashari et al 2002). Platelets express TLR2, 4, and 9 (Aslam et al 2006;Clark et al 2007).…”

Section: Platelet−derived Products and Function In Host Defensementioning

confidence: 99%

Platelet influence on T- and B-cell responses

Sowa

Crist

Ratliff

et al. 2009

Arch. Immunol. Ther. Exp.

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Understanding the adaptive immune response is an area of research critically important in medicine. Several positive regulators of B- and T-cell activation exist to eliminate pathogens, in which CD40 ligand (CD154) plays a fundamental role. It is well documented that CD154 expressed by CD4 T helper cells can be critical in the proper activation of dendritic cells for the productive stimulation of CD8 T cells and is required for proper T-dependent B-cell immunity. However, platelets are an abundant and systemic source of CD154. While classically known to be important for hemostasis and inflammation, several lines of evidence suggest that platelet-derived ligands can modulate the adaptive immune compartment.

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Platelet-platelet and platelet-leukocyte interactions induced by outer membrane vesicles from N. meningitidis

Abstract: Meningococcal-derived OMVs as well as purified meningococcal LPS, contribute to increased platelet-platelet and platelet-leukocyte aggregation and may thus be of great importance in the development of microthrombosis and organ dysfunction related to fulminant meningococcal septicemia.

Cited by 29 publications

References 18 publications

Platelets express functional Toll-like receptor-4

Platelets express functional Toll-like receptor-4

Exou-Induced Vascular Hyperpermeability and Platelet Activation in the Course of Experimental Pseudomonas Aeruginosa Pneumosepsis

Platelet influence on T- and B-cell responses

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