Heme induces human and mouse platelet activation through C-type-lectin-like receptor-2

Bourne, Joshua H.; Colicchia, Martina; Di, Ying; Martin, Eleyna M.; Slater, Alexandre; Roumenina, Lubka T.; Dimitrov, Jordan D.; Watson, Steve P.; Rayes, Julie

doi:10.3324/haematol.2020.246488

Cited by 56 publications

(46 citation statements)

References 15 publications

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“…The activation of this pathway in platelets is generally seen along with other platelet receptor-ligand interactions, such as GP1bαIX-vWF and GPVI-collagen [197,198]. In addition to GP1bα, heme can induce platelet activation through C-type lectin like receptor-2 (CLEC-2) [199]. Heme up-regulates and binds to TF on macrophages as well, promoting TF-dependent coagulation activation [200].…”

Section: Rbcs As a Major Source Of Oxidative Stress-associated Thrombmentioning

confidence: 99%

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Wang

Zennadi

2020

IJMS

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Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of ROS within the red blood cell (RBC) in initiating venous thrombosis during aging. Growing evidence has shifted our interest in the role of unjustifiably unvalued RBCs in blood coagulation. RBCs can be a major source of oxidative stress during aging, since RBC redox homeostasis is generally compromised due to the discrepancy between prooxidants and antioxidants. As a result, ROS accumulate within the RBC due to the constant endogenous hemoglobin (Hb) autoxidation and NADPH oxidase activation, and the uptake of extracellular ROS released by other cells in the circulation. The elevated RBC ROS level affects the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability. These changes impair RBC function in hemostasis and thrombosis, favoring a hypercoagulable state through enhanced RBC aggregation, RBC binding to endothelial cells affecting nitric oxide availability, RBC-induced platelet activation consequently modulating their activity, RBC interaction with and activation of coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles, accelerated aging and hemolysis. Thus, RBC oxidative stress during aging typifies an ultimate mechanism in system failure, which can affect major processes involved in the development of venous thrombosis in a variety of ways. The reevaluated concept of the critical role of RBC ROS in the activation of thrombotic events during aging will help identify potential targets for novel strategies to prevent/reduce the risk for VT/E or VT/E recurrences in mid-life stage adults.

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Section: Rbcs As a Major Source Of Oxidative Stress-associated Thrombmentioning

confidence: 99%

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Wang

Zennadi

2020

IJMS

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“…CLEC-2 is a hemi-immunoreceptor tyrosine-based activation motif (hemi-ITAM) receptor constitutively expressed on platelets and a sub-set of dendritic cells. CLEC-2 induces platelet activation through its interaction with its endogenous ligands podoplanin or heme (16,17). Podoplanin is a small, transmembrane O-glycosylated mucin-type protein constituently expressed on type I lung epithelial cells, fibroblastic reticular cells, lymphatic endothelial cells and podocytes, and is upregulated on inflammatory macrophages, TH17 cells, fibroblasts and cancer cells (18,19).…”

Section: Introductionmentioning

confidence: 99%

CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis

Bourne

Beristain‐Covarrubias

Zuidscherwoude

et al. 2021

Front. Immunol.

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Platelets play a key role in the development, progression and resolution of the inflammatory response during sterile inflammation and infection, although the mechanism is not well understood. Here we show that platelet CLEC-2 reduces tissue inflammation by regulating inflammatory macrophage activation and trafficking from the inflamed tissues. The immune regulatory function of CLEC-2 depends on the expression of its ligand, podoplanin, upregulated on inflammatory macrophages and is independent of platelet activation and secretion. Mechanistically, platelet CLEC-2 and also recombinant CLEC-2-Fc accelerates actin rearrangement and macrophage migration by increasing the expression of podoplanin and CD44, and their interaction with the ERM proteins. During ongoing inflammation, induced by lipopolysaccharide, treatment with rCLEC-2-Fc induces the rapid emigration of peritoneal inflammatory macrophages to mesenteric lymph nodes, thus reducing the accumulation of inflammatory macrophages in the inflamed peritoneum. This is associated with a significant decrease in pro-inflammatory cytokine, TNF-α and an increase in levels of immunosuppressive, IL-10 in the peritoneum. Increased podoplanin expression and actin remodelling favour macrophage migration towards CCL21, a soluble ligand for podoplanin and chemoattractant secreted by lymph node lymphatic endothelial cells. Macrophage efflux to draining lymph nodes induces T cell priming. In conclusion, we show that platelet CLEC-2 reduces the inflammatory phenotype of macrophages and their accumulation, leading to diminished tissue inflammation. These immunomodulatory functions of CLEC-2 are a novel strategy to reduce tissue inflammation and could be therapeutically exploited through rCLEC-2-Fc, to limit the progression to chronic inflammation.

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“…6,40 Moreover, the presence of elevated serum sP-selectin also reflects upon enhanced haem-driven platelet activation during clotting formation, as recently demonstrated. 88 NO availability is severely reduced in patients with SCD and b-thal major, as suggested by reduced nitrotyrosine levels that likely reflect upon reduced NO production by endothelial NO synthase (Fig 4). NO plays a major role in vascular homeostasis and is a critical regulator of vasomotor tone, endothelial adhesion molecule expression and platelet activation.…”

Section: Discussionmentioning

confidence: 98%

Vasculo‐toxic and pro‐inflammatory action of unbound haemoglobin, haem and iron in transfusion‐dependent patients with haemolytic anaemias

et al. 2021

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Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with b-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem-and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor a (TNFa) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFa levels, b-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.

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Heme induces human and mouse platelet activation through C-type-lectin-like receptor-2

Cited by 56 publications

References 15 publications

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis

Vasculo‐toxic and pro‐inflammatory action of unbound haemoglobin, haem and iron in transfusion‐dependent patients with haemolytic anaemias

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