Thrombocytopenia impairs host defense in gram-negative pneumonia–derived sepsis in mice

Stoppelaar, Sacha F de; Veer, Cornelis van ’t; Claushuis, Theodora A. M.; Albersen, Bregje J. A.; Roelofs, Joris J. T. H.; Poll, Tom van der

doi:10.1182/blood-2014-05-573915

Cited by 187 publications

(261 citation statements)

References 47 publications

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“…Platelets have been shown to dampen leucocyte activation and pro‐inflammatory cytokine production in both mouse models of sepsis14 and in vitro cell models of infection,15, 16 and this platelet effect is associated with host defence and survival in sepsis 17, 18. The regulatory effect of platelets has largely been characterised in peripheral blood mononuclear cells (PBMCs) in vitro exposed to lipopolysaccharide (LPS; a TLR4 agonist), or in mouse models of sepsis 14, 17, 19, 20. However, the ability of platelets to affect the leucocyte response to a wider range of TLR agonists has not been fully characterised.…”

Section: Introductionmentioning

confidence: 99%

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

et al. 2018

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ObjectivesPlatelets are important regulators of vascular thrombosis and inflammation and are known to express Toll‐like receptors (TLRs). Through TLRs, platelets mediate a number of responses by interacting with leucocytes. Here, we report the extent to which platelets modulate in vitro peripheral blood mononuclear cells (PBMCs) and granulocyte responses to TLR4, TLR2/1 and TLR2/6 stimulation in healthy subjects.MethodsPeripheral blood mononuclear cells and granulocytes from 10 healthy volunteers were cultured alone or cocultured with platelets. Cultures were left unstimulated or stimulated with 1 or 100 ng mL−1 of either LPS (TLR4 agonist), Pam3CSK4 (TLR2/1 agonist) or fibroblast‐stimulating lipopeptide (FSL)‐1 (TLR2/6 agonist). Neutrophil activation (CD66b expression), monocyte activation (HLA‐DR), granulocyte elastase production and PBMC cytokine and chemokine production were examined.ResultsPlatelet coculture decreased neutrophil CD66b expression in response to LPS, Pam3CSK4 and FSL‐1, and modestly decreased monocyte HLA‐DR expression in response to low‐dose LPS. Platelets reduced granulocyte elastase secretion in response to low doses of all TLR agonists tested. In response to LPS, platelet coculture reduced IL‐6, tumor necrosis factor (TNF)‐α and MIP‐1β production, and increased IL‐10 production by PBMCs. In response to FSL‐1, platelets increased IL‐6, IL‐10 and MIP‐1β production, but reduced TNF‐α production. Platelet coculture did not alter PBMC cytokine/chemokine production in response to Pam3CSK4.ConclusionThis study challenges the notion that platelets act solely in a pro‐inflammatory manner. Rather, platelets are complex immunomodulators that regulate leucocyte responses to TLR stimulation in a TLR agonist‐specific manner. Platelets may modulate leucocyte responses to dampen inflammation, and this platelet effect may play an important role in reducing inflammation‐mediated host damage.

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Section: Introductionmentioning

confidence: 99%

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

et al. 2018

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“…Sepsis-induced elevation of 5-HT has recently been discovered in a mouse model where high levels of 5-HT facilitated endothelial hyperpermeability [3]. Microvascular dysfunction is believed to contribute to patient mortality in sepsis [7]. Therefore an intervention with a 5-HT transporter inhibitor was speculated to be a potential therapeutic option [3].…”

Section: Introductionmentioning

confidence: 99%

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Meier

Ottiger

Vögeli

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: As part of the immune defense during infection, an increase in enzyme activity of indoleamine 2,3-dioxygenase (IDO) leads to a breakdown of tryptophan to kynurenine. In previous animal studies, therapeutic antagonism of IDO resulted in reduced sepsis mortality. We investigated the prognostic ability of tryptophan, serotonin, kynurenine and IDO (represented by the ratio of kynurenine/tryptophan) to predict adverse clinical outcomes in patients with community-acquired pneumonia (CAP). Methods: We measured tryptophan, serotonin and kynurenine on admission plasma samples from CAP patients included in a previous multicenter trial by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We studied their association with inflammation (C-reactive protein), infection (procalcitonin) and clinical outcome. Results: Mortality in the 268 included patients was 45% within 6 years of follow-up. IDO and kynurenine showed a

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“…The direct contribution of FOG to bacterial dissemination and pathogenesis of infection was not investigated in our animal model, since the focus of our hypothesis was the contribution of platelet activation and aggregation to the pathogenesis of GGS infection. Platelets have been reported to contribute to the pathogenesis of GAS infection in an animal model (Kahn et al, 2013); however, platelets have also been proposed to protect in an animal model of sepsis (de Stoppelaar et al, 2014;Xiang et al, 2013). Interestingly, studies of human sepsis patients indicate that antiplatelet therapy is beneficial for the outcome of invasive infection (Winning et al, 2009;Otto et al, 2013;Akinosoglou & Alexopoulos, 2014).…”

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confidence: 99%

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

2016

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Platelets have been reported to become activated in response to bacteria and this is proposed to contribute to the acute response to bacterial infection. In the present study, we investigated platelet aggregation in response to group G streptococci (GGS) in vitro in healthy human donors and in vivo in a mouse model of streptococcal sepsis. Platelet aggregation by GGS was dependent on the bacterial surface protein FOG and engagement of the platelet fibrinogen receptor; however, it was independent of IgG and the platelet Fc receptor. Platelets exerted no antibacterial effects on the bacteria, and aggregates formed were markedly unstable, allowing bacteria to rapidly return to the plasma and grow post-aggregation. Thrombocytopenia and platelet activation occurred during invasive infection with GGS, and platelets were demonstrated to contribute to bacterial dissemination during infection. These findings reveal an important role for bacteria-platelet interactions during the pathogenesis of streptococcal infection.

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Thrombocytopenia impairs host defense in gram-negative pneumonia–derived sepsis in mice

Abstract: Key Points Severe thrombocytopenia is associated with a strongly impaired host defense during pneumonia-derived Klebsiella pneumoniae sepsis. Platelet counts between 5 and 13 × 109/L of normal prevent bleeding and confer protection against distant organ damage during gram-negative sepsis.

Cited by 187 publications

References 47 publications

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

Platelets regulate leucocyte responses to Toll‐like receptor stimulation

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

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