Macrophage scavenger receptor SR-AI contributes to the clearance of von Willebrand factor

Wohner, Nikolett; Muczynski, Vincent; Mohamadi, Amel; Legendre, Paulette; Proulle, Valérie; Aymé, Gabriel; Olivier, Christophe; Lenting, Peter J.; Denis, Cécile V.; Casari, Caterina

doi:10.3324/haematol.2017.175216

Cited by 39 publications

(40 citation statements)

References 31 publications

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“…We observed a substantial reduction in the titer of total anti-human VWF IgG antibodies in STAB2-KO mice compared with normal involving a number of ligand-receptor interactions including the hepatocyte-and macrophage-expressed asialoglycoprotein receptor, SIGLEC5, SR-A1, and members of the LDL receptor family (12,29,(41)(42)(43)(44). In immunological studies, FVIII has been shown to associate in part with both dendritic cells and marginal zone macrophages in the mouse spleen (10,11), while the binding of FVIII to dendritic cell receptors has been described in vitro (45).…”

Section: Genetic Variability and N-linked Glycans Modulate The Interamentioning

confidence: 84%

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Swystun¹,

Lai²,

Notley³

et al. 2018

Journal of Clinical Investigation

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variants demonstrated that the STAB2 p.E2377K variant associates with a 33.6% and 26.8% increase in VWF and FVIII levels, respectively (25), suggesting that stabilin-2 is a significant regulator of plasma VWF-FVIII levels. Based on its known function and association with plasma VWF levels, stabilin-2 may act as a clearance receptor for VWF and/or FVIII; however, the mechanistic basis for this relationship has not been assessed.In addition to facilitating protein clearance, binding of VWF-FVIII to endocytic receptors can regulate interactions with cells in the immune system. The development of FVIII neutralizing antibodies (termed inhibitors) in response to infused FVIII replace-STAB2 encodes stabilin-2, a class H scavenger receptor expressed on the sinusoidal endothelial cells of the liver, spleen, and lymphatics that functions as a clearance receptor for hyaluronic acid and other glycosaminoglycans (21-23). Stabilin-2 is composed of repetitive extracellular fasciclin and EGF-like domains with a single X-link domain that is C-type lectin-like, located near its transmembrane region. Subsequent to the CHARGE study, additional GWAS-based publications have independently confirmed that common STAB2 variants associate with plasma

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Section: Genetic Variability and N-linked Glycans Modulate The Interamentioning

confidence: 84%

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Swystun¹,

Lai²,

Notley³

et al. 2018

Journal of Clinical Investigation

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“…In keeping with the importance of shear, the A1 domain of VWF has been shown to be important in modulating interaction with LRP1 (Wohner et al , ; Chion et al , ). In vitro studies further suggest that additional domains of VWF (including D'D3 and D4) may also contribute to LRP1 binding (Wohner et al , ) (Fig B). Although the molecular mechanisms through which multimeric VWF interacts with the large LRP1 receptor remain poorly understood, plasma VWF levels were significantly increased (1·6‐fold) in mice with macrophage‐specific deficiency of LRP1 compared to controls (Rastegarlari et al , ).…”

Section: Scavenger Receptors and Vwf Clearancementioning

confidence: 97%

“…The scavenger receptor class A member I (SR‐A1; also known as SCARA1 or CD204) is another scavenger receptor expressed in macrophages and DCs (Zani et al , ) (Fig A). Recent in vitro studies have demonstrated that VWF binds to purified SR‐A1 in a dose‐dependent and saturable manner (Wohner et al , ). Similar to LRP1, multiple different domains of VWF have been implicated in regulating SR‐A1 binding (including the D'D3 region, the A1 domain and the D4 domain) (Wohner et al , ) (Fig B).…”

Section: Scavenger Receptors and Vwf Clearancementioning

confidence: 99%

“…Recent in vitro studies have demonstrated that VWF binds to purified SR‐A1 in a dose‐dependent and saturable manner (Wohner et al , ). Similar to LRP1, multiple different domains of VWF have been implicated in regulating SR‐A1 binding (including the D'D3 region, the A1 domain and the D4 domain) (Wohner et al , ) (Fig B). However, in marked contrast to LRP1, binding of VWF to SR‐A1 can occur under static conditions, without the need for either shear stress or ristocetin.…”

Section: Scavenger Receptors and Vwf Clearancementioning

confidence: 99%

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von Willebrand factor clearance – biological mechanisms and clinical significance

et al. 2018

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The mechanisms involved in regulating von Willebrand factor (VWF) clearance remain poorly understood. However recent studies have shown that macrophages play a critical role in regulating the half-life of VWF, and have identified specific lectin (including asialoglycoprotein, macrophage galactose-type lectin, Sigec-5 and C-type lectin domain family 4 member M) and scavenger receptors (including low-density lipoprotein receptor-related protein-1, scavenger receptor A1 and stabilin-2) that are involved in VWF clearance. Further studies will be required to determine the relative importance of these individual receptors with respect to physiological and pathological VWF clearance. Nevertheless, recent clinical data have highlighted the importance of enhanced VWF clearance in the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, increased clearance also contributes to reduced VWF levels in many patients with type 2 and type 3 VWD. Improved understanding regarding VWF clearance is not only of direct biological relevance, but may also have important implications for the development of novel therapeutic agents with extended plasma half-lives for the treatment of both VWD and haemophilia A.

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“…In this regard, VWF mutations associated with decreased VWF sialylation [59] and increased binding of VWF to LRP1 and SR-AI [60,61] have been associated with low VWF resembling the type 1 VWD phenotype, but with normal platelet and endothelial VWF [58]. Supporting these observations, large cohort studies have found a significant proportion of type 1 VWD patients with enhanced VWF clearance [39,62,63], which would be an additional mechanism of the disease.…”

Section: Difficulties With Diagnosis Of Type 1vwdmentioning

confidence: 99%

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

Mezzano

Quiroga

2019

Journal of Thrombosis and Haemostasis

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Summary The best‐known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA‐100/200) lack sensitivity and, like BSs, are not disease‐specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut‐off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.

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Macrophage scavenger receptor SR-AI contributes to the clearance of von Willebrand factor

Cited by 39 publications

References 31 publications

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

von Willebrand factor clearance – biological mechanisms and clinical significance

Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research

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