Hepatocytes clear platelets and are key regulators of disseminated intravascular coagulation during sepsis☆
Article Outline
The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Grewal PK, Uchiyama S, Ditto D, Varki N, Le DT, Nizet V, Marth JD.
The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium’s neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.
[Abstract reproduced by permission of Nat Med 2008;14:648–655]
Sepsis remains a major problem in intensive care therapy affecting more than half a million individuals annually and is one of the leading causes of death in intensive care units, with mortality rates as high as 30–50% [1]. Activation of the coagulation cascade in sepsis leading to disseminated intravascular coagulation (DIC) is an essential component in the development of multi-organ failure and is associated with increased mortality [2]. Thrombocytopenia is frequent in septic patients, however, the underlying mechanisms are only partly understood.
A recent report by Grewal et al. demonstrated that the clearance of circulating platelets during DIC in sepsis takes place in the liver [3]. Using a murine model of Streptococcus pneumoniae-induced sepsis, they showed that this process was mediated by the Ashwell receptor, an asialoglycoprotein receptor expressed on hepatocytes.
The Ashwell receptor was originally discovered by Gilbert Ashwell and colleagues in 1974 [4], [5]. It is composed of two glycoprotein receptor subunits (Asgpr-1; Asgpr-2) and recognizes glycoproteins lacking sialic acid called asiologlycoproteins. Located on the hepatocyte cell surface, it is able to rapidly remove potentially deleterious asiologlycoproteins from the circulation [6]. Although first described over thirty years ago, the biological significance of the Ashwell receptor has long remained elusive. Endogenous ligands for the Ashwell receptor were only recently found when Ellies et al. discovered that desialylated platelets and the von Willebrand factor (vWF) can be removed from the circulation by hepatic asialoglycoprotein receptors [7]. They characterized a genetic lesion that inactivated the murine sialyltransferase (ST3Gal-IV). Sialyltransferases are enzymes which add sialic acid to glycoprotein, thereby masking possible endogenous ligands of the Ashwell protein receptor. Mice deficient in sialyltransferase (ST3Gal-IV) displayed spontaneously decreased vWF levels and reduced platelet numbers causing prolonged bleeding and coagulation times [7]. Based on these findings, Grewal et al. investigated the relevance of this mechanism in sepsis-induced DIC.
Using mice deficient in either of the subunits of the Ashwell receptors (Asgpr-1; Asgpr-2), the authors demonstrated that the reduction in vWF in ST3Gal-IV deficient mice was dependent on the Asgr-1 subunit. In contrast, depletion of platelets required both subunits of the Ashwell receptor. Moreover, they identified the bacterial NanA neuraminidase as the sialidase responsible for platelet desialylation in S. pneumoniae sepsis. The Ashwell receptor then promotes clearance of the desialylated platelets in S. pneumoniae sepsis protecting the host from overshooting DIC. A mutant S. pneumoniae strain lacking in sialidase activity failed to produce asialyted platelets and subsequent thrombocytopenia. NanA deficient S. pneumoniae mutants caused a more severe coagulopathy than NanA expressing strains. Likewise, Asgr-1 deficient mice did not develop thrombocytopenia but suffered from considerably aggravated coagulopathy accompanied by increased mortality. These findings show that the Ashwell receptor is, therefore, critical for moderating the severity of DIC during S. pneumoniae sepsis. It reveals that thrombocytopenia in sepsis due to S. pneumoniae infection is neither mediated only by the pathogen itself, nor by platelet consumption due to DIC.
The discovery of this crucial role of the Ashwell receptor on hepatocytes not only opens a new view on DIC, but it demonstrates a further essential regulatory function of the liver in septic conditions. Hepatocytes, as the major source of coagulation factors actively regulate intravascular coagulation by clearing platelets and also vWF from circulation via the Ashwell receptor. Detection and clearance of desialylated glycoproteins and platelets also enable hepatocytes to indirectly sense the presence of a S. pneumoniae infection, which could probably have further consequences than regulating DIC. This intriguing function could define asialoglycoprotein receptors as a novel class of danger receptors. Neuraminidase NanA is an essential virulence factor in all S. pneumoniae isolates and is required for Ashwell receptor-mediated thrombocytopenia. Other respiratory pathogens, including P. aeruginosa and H. influenzae also express neuraminidase, which facilitates mucosal infection [8]. Exploiting NanA activity to regulate DIC severity of sepsis through Ashwell receptor commitment, reveals an interesting new strategy in host-pathogen interaction. However, many bacteria lack NanA expression, indicating alternative pathways leading to thrombocytopenia in DIC. Furthermore, the Ashwell receptor is not the only asialoglycoprotein receptor [9]. Moreover, it has yet not been determined whether the present findings are also valid for the human system. There are, of course, a number of pathways involved in the coagulation cascade leading to DIC, but the Ashwell receptor could represent a promising, novel therapeutic target in sepsis associated coagulopathy. Overactivation of this pathway by pharmacological intervention would, however, hold obvious risks, and more research on the function and regulation of asialoglycoprotein receptors is needed. The re-discovery of the Ashwell receptor once again highlights the central role of the liver in regulating host homeostasis during bacterial infections and sepsis.
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☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.
PII: S0168-8278(09)00138-X
doi:10.1016/j.jhep.2009.02.008
© 2009 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
