Platelet-Derived MRP-14 Induces Monocyte Activation in Patients With Symptomatic Peripheral Artery Disease

Dann, Rebecca; Hadi, Tarik; Montenont, Emilie; Boytard, Ludovic; Alebrahim, Dornaszadat; Feinstein, Jordyn; Allen, Nicole; Simon, Robert I.; Barone, Krista; Uryu, Kunihiro; Guo, Yu; Rockman, Caron; Ramkhelawon, Bhama; Berger, Jeffrey S.

doi:10.1016/j.jacc.2017.10.072

Cited by 53 publications

(69 citation statements)

References 35 publications

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“…The NLRP3 inflammasome is primarily assembled in myeloid cells. Although activated platelets are known to form aggregates with immune cells and modulate their function (Allen et al, 2019; Dann et al, 2018; Kral et al, 2016; Passacquale et al, 2011b) the effect of platelets on inflammasome activation in innate immune cells remains unexplored. To address this question, we investigated the influence of platelets on the production of IL-1 cytokines elicited by the bona fide NLRP3 inflammasome activators Nigericin and ATP in mouse and human immune cells.…”

Section: Resultsmentioning

confidence: 99%

“…In the last decade, platelets have been increasingly recognized of their roles in immunity (Allen et al, 2019; Dann et al, 2018; Kral et al, 2016; Passacquale et al, 2011a). Approximately one trillion platelets (150– 450 × 10 9 /L) circulate in the blood of a healthy individual, a number that surpasses all other leukocytes in the vasculature by several folds.…”

Section: Introductionmentioning

confidence: 99%

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Platelets fuel the inflammasome activation of innate immune cells

Rolfes

Ribeiro

Hawwari

et al. 2019

Preprint

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ABSTRACTThe inflammasomes control the bioactivity of pro-inflammatory cytokines of the interleukin (IL)-1 family. The inflammasome assembled by NLRP3 has been predominantly studied in homogenous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets, the second most abundant cells in the blood, boost the inflammasome capacity of human macrophages and neutrophils, and are critical for IL-1 production by monocytes. Platelets license NLRP3 transcription, thereby enhancing ASC nucleation, caspase-1 activity, and IL-1β maturation. Platelet depletion attenuated LPS-induced IL-1β in vivo, and platelet counts correlate with plasma concentrations of IL-1β in malaria patients. Furthermore, a platelet gene signature was enriched among the highest expressed transcripts in IL-1β-driven autoinflammatory diseases. The platelet-mediated enhancement of inflammasome activation was independent of cell-to-cell contacts, platelet-derived lipid mediators, purines, nucleic acids and a host of platelet cytokines, and involved the triggering of calcium sensing receptors on macrophages by a calcium-dependent protein commonly released by platelets and megakaryocytes. Finally, we report that platelets provide an additional layer of regulation of inflammasomes in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Platelets fuel the inflammasome activation of innate immune cells

Rolfes

Ribeiro

Hawwari

et al. 2019

Preprint

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“…Anti-platelet therapy for patients following a diagnosis of MI consists of aspirin and a P2Y 12 receptor antagonists irrespective of whether the diagnosis is STEMI or NSTEMI. Recent data conducted in humans and in relevant murine models of MI and peripheral arterial disease (PAD) suggests the platelet phenotype, platelet receptor signaling, and responsiveness to antiplatelet medications are quite different from healthy platelets in which anti-platelet agents are first characterized (1)(2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

Kim

Auerbach

Sadhra

et al. 2019

Preprint

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Word Count: abstract 244 (abstract), 3639 (main) ABSTRACT BACKGROUND: A Sex-specific, personalized approach to anti-platelet therapy may be important in patients with myocardial infarction (MI). OBJECTIVES:Our goal was to determine whether platelets activate differently in healthy men and women compared to following MI. METHODS:Blood was obtained from healthy subjects or patients presenting acutely with STsegment Elevation Myocardial Infarction (STEMI) and non-ST Segment Elevation Myocardial Infarction (NSTEMI). Platelet function through surface receptor activation was examined in healthy subjects, in patients with MI, and in age-and strain-matched mice before and after MI.Multivariate regression analyses revealed clinical variables associated with platelet receptor sensitivity at the time of MI. RESULTS:Platelets from healthy women are dose-dependently more active compared to men, particularly through the platelet thromboxane signaling pathway (7.8-fold increase in women vs.3.0-fold in men, P=0.02). At the time of MI, platelet activation through surface proteaseactivated receptor 1 (PAR1) was less in women than men (3.5-fold vs. 8.5-fold, respectively, P=0.0001). Multivariate regression analyses revealed male sex (P=0.04) and NSTEMI (P=0.003) as independent predictors of enhanced platelet PAR1 signaling at the time of MI. Similar to humans, healthy female mice showed preferential thrombin-mediated platelet activation compared to male mice (8.7-fold vs. 4.8-fold, respectively; P<0.001). In the immediate post-MI environment, male mice showed preferential thrombin-mediated platelet activation compared to female mice (12.4-fold vs. 5.5-fold, respectively; P<0.001).3 CONCLUSIONS: These results outline a previously unrecognized sex-dependent platelet phenotype where inhibition of thrombin signaling in the peri-MI environment-particularly in males-may be an important consideration. CONDENSED ABSTRACTPreclinical studies evaluating anti-platelet drugs are generally conducted in platelets isolated from healthy individuals. Growing evidence suggests changes in platelet signaling properties in certain disease conditions compared to healthy platelets may alter the response to anti-platelet medications. This investigation revealed that platelets from men and women who are healthy and following MI signal differently, particularly through thromboxane and PAR1 receptors. This effect was especially noted in patients with NSTEMI compared to STEMI. These observations raise the possibility of considering a sex-specific anti-platelet regimen for males and females in atheroembolic vascular diseases such as NSTEMI..

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“…Generally, platelet decline is closely associated with inflammatory disease caused by the increased activation of platelet and subsequent sequestration of platelets in cell-cell interactions such as MPAs [ 33 ]. Upon platelet activation, the expression of P-selectin is augmented and MPAs are thereby enhanced leading to the reprogrammed monocyte activation through enriching MRP-14 protein [ 34 ]. Accompanied by the activation of monocytes, the content of MPAs and the expression of CD11b on monocytes are both promoted in atrial fibrillation (AF) patients with thrombus formation [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Papain Ameliorates the MPAs Formation-Mediated Activation of Monocytes by Inhibiting Cox-2 Expression via Regulating the MAPKs and PI3K/Akt Signal Pathway

Fei

Yuan

Zhao

et al. 2018

BioMed Research International

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Monocytes activation and subsequent inflammatory response mediated by monocyte-platelet aggregates (MPAs) formation play the key roles in the early pathogenesis of atherosclerosis (AS). Exploration of novel drugs to ameliorate MPAs formation-mediated monocytes activation would be helpful for the treatment of AS patients. Papain has definite pharmacological effects including antiplatelet, thrombolysis, and anti-inflammation. However, its effect on MPAs formation and the following monocytes activation remains vague. This study aimed to illustrate the underlying mechanisms of papain on MPAs formation-initiated monocytes activation in vitro. In this study, Papain, Cox-2 inhibitor (NS-398), and NF-κB agonist (TNF-α) were used as the treating agents, respectively. MPAs formation and activated monocytes were measured by flow cytometry (FCM). Cox-2 mRNA, MCP-1, and proteins of Cox-2 and NF-κB signal pathway were detected by qRT-PCR, ELISA, and western blotting, respectively. As we observed, papain exhibited the powerful inhibitory effects on thrombin-mediated MPAs formation and monocytes activation in a concentration-dependent manner as what Cox-2 inhibitor demonstrated. However, the inhibitory tendency was significantly reversed by TNF-α. We also discovered that both Cox-2 mRNA and protein expression as well as the release of MCP-1 of monocyte was inhibited by either papain or NS-398, but TNF-α stimulated Cox-2 expression and release of MCP-1. The results of western blotting assay indicated that thrombin-mediated proteins expression of MAPKs and PI3K/Akt signal pathway was inhibited by papain and NS-398. However, TNF-α notably abated the inhibitory effects of papain on the process of MPAs-initiated monocytes activation. Our findings suggest that papain can inhibit the MPAs formation-mediated activation of monocytes by inhibiting the MAPKs and PI3K/Akt signal pathway.

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Platelet-Derived MRP-14 Induces Monocyte Activation in Patients With Symptomatic Peripheral Artery Disease

Cited by 53 publications

References 35 publications

Platelets fuel the inflammasome activation of innate immune cells

Platelets fuel the inflammasome activation of innate immune cells

A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

Papain Ameliorates the MPAs Formation-Mediated Activation of Monocytes by Inhibiting Cox-2 Expression via Regulating the MAPKs and PI3K/Akt Signal Pathway

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