Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab – preclinical and clinical studies

Kling, Dorothée; Stucki, Corinne; Kronenberg, Sven; Tuerck, Dietrich; Rhéaume, Éric; Tardif, Jean‐Claude; Gaudreault, Jacques; Schmitt, Christophe

doi:10.1016/j.thromres.2013.02.020

Cited by 41 publications

(36 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 Interestingly, recent results from preclinical and clinical studies suggest that administration of a novel anti-P-selectin antibody suppresses plateletleukocyte interactions and represents a promising approach to target the early onset and progression of atherosclerosis. 36 We further found that platelets preferably bound to the nonclassical and intermediate monocyte subsets and also observed a shift toward CD16 + monocytes in the presence of platelets and OxLDL. These observations are in line with previous reports, showing P-selectin-PSGL-1 interactions to be sufficient to trigger phenotypic changes toward proinflammatory CD16 + monocytes, which lead to increased endothelial adhesiveness.…”

Section: Discussionmentioning

confidence: 50%

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

Badrnya

Schrottmaier

Kral

et al. 2014

ATVB

133

115

View full text Add to dashboard Cite

Objective-A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet-monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. Approach and Results-Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet-monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet-monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36-OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet-monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet-monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR −/− mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. Conclusions-Our results on OxLDL-mediated platelet-monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.

show abstract

Section: Discussionmentioning

confidence: 50%

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

Badrnya

Schrottmaier

Kral

et al. 2014

ATVB

133

115

View full text Add to dashboard Cite

show abstract

“…Inclacumab, an anti-P-selectin antibody, hinders the formation of platelet-monocyte aggregates and thereby prevents the inflammatory burst of these interactions. 46 Likewise, acute coronary syndromes are characterized by intense neutrophil activation. Recent studies report that this activation is induced by platelet-P selectin interactions inducing complete myeloperoxidase depletion in neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

Gerdes

Seijkens

Lievens

et al. 2016

ATVB

View full text Add to dashboard Cite

Objective— Beyond their eminent role in hemostasis and thrombosis, platelets are recognized as mediators of inflammation. Platelet cluster of differentiation 40 (CD40) ligand (CD40L and CD154) plays a key role in mediating platelet-induced inflammation in atherosclerosis. CD40, the receptor for CD40L, is present on platelets; however, the role of CD40 on this cell type is until now undefined. Approach and Results— We found that in both mice and humans, platelet CD40 mediates the formation of platelet–leukocyte aggregates and the release of chemokine (C-X-C motif) ligand 4. Leukocytes were also less prone to adhere to CD40-deficient thrombi. However, platelet CD40 was not involved in platelet aggregation. Activated platelets isolated from Cd40 −/− Apoe −/− mice adhered less to the endothelium upon injection into Apoe −/− mice when compared with CD40-sufficient platelets. Furthermore, lack of CD40 on injected platelets led to reduced leukocyte recruitment to the carotid artery as assayed by intravital microscopy. This was accompanied by a decrease in endothelial vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule, VE-cadherin, and P-selectin expression. To investigate the effect of platelet CD40 in atherosclerosis, Apoe −/− mice received thrombin-activated Apoe −/− or Cd40 −/− Apoe −/− platelets every 5 days for 12 weeks, starting at the age of 17 weeks, when atherosclerotic plaques had already formed. When compared with mice that received Apoe −/− platelets, those receiving Cd40 −/− Apoe −/− platelets exhibited a >2-fold reduction in atherosclerosis. Plaques of mice receiving CD40-deficient platelets were less advanced, contained less macrophages, neutrophils, and collagen, and displayed smaller lipid cores. Conclusions— Platelet CD40 plays a crucial role in inflammation by stimulating leukocyte activation and recruitment and activation of endothelial cells, thereby promoting atherosclerosis.

show abstract

“…In a study of percutaneous coronary intervention in patients with non-ST-segment elevation myocardial infarction, high doses of the specific P-selectin antagonist, inclacumab, reduced the extent of myocardial injury (measurements of troponin I and creatine kinase-myocardial band) (41). The underlying mechanism of action of inclacumab in vivo remains to be determined, although inclacumab treatment reduced the levels of soluble P-selectin (41), and a recent study demonstrated that inclacumab reduced the formation of platelet-leukocyte and platelet-monocyte complexes both in vitro and in vivo, as well as leukocyte aMb2 activation detected by mAb CBRM1/5 (42). It would be interesting to investigate the impact of P-selectin antagonism on the acquisition of a proinflammatory monocyte phenotype in vivo.…”

Section: Discussionmentioning

confidence: 99%

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

Stephen

Emerson

Fox

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Induction of an inflammatory monocyte phenotype by activated platelets is implicated in the pathogenesis of inflammatory diseases, including atherosclerosis. In this study, we investigated the early signaling events associated with this platelet-induced inflammatory phenotype. We report that coculture of human monocytes with activated platelets induces phosphorylation of Akt, together with rapid mobilization of intracellular Ca2+, and show that these signaling events can be uncoupled from monocyte binding to activated platelets. Specifically, Ab-inhibition studies and incubation of monocytes with activated platelet supernatant highlighted a role for secreted product(s) of activated platelets. We also identified a role for pertussis toxin–sensitive G protein–coupled receptors and excluded key candidates platelet-activating factor receptor and CCR5. Our results suggest that inhibition of monocyte–platelet interactions via PSGL-1 or P-selectin is not sufficient to prevent platelet-mediated monocyte activation in an inflammatory context. These findings have important implications for the development of therapeutics to treat diseases in which platelet–monocyte complexes are implicated in pathogenesis.

show abstract

Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab – preclinical and clinical studies

Cited by 41 publications

References 44 publications

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes

The Uncoupling of Monocyte–Platelet Interactions from the Induction of Proinflammatory Signaling in Monocytes

Contact Info

Product

Resources

About