The Ashwell receptor mitigates the lethal coagulopathy of sepsis

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Abstract

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.

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Figure 1: Ashwell receptors of hepatocytes modulate vWF homeostasis and blood coagulation.
Figure 2: The Ashwell receptor and the ST3Gal-IV sialyltransferase participate in platelet clearance.
Figure 3: Thrombocytopenia caused by NanA-dependent platelet desialylation and Ashwell receptor function in S. pneumoniae infection.
Figure 4: Extension of lifespan and reduction in coagulopathy by the Ashwell receptor in lethal S. pneumoniae infection.
Figure 5: Increased severity of coagulopathy in sepsis after infection with the S. pneumoniae NanA mutant.
Figure 6: The Ashwell receptor decreases mortality in S. pneumoniae sepsis.

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Acknowledgements

We thank L. Brown and Q. Chen for technical assistance with some of the experiments. Assistance with fluorescent microscopy was obtained from the University of California, San Diego Cancer Center Digital Imaging Shared Resource team directed by J. Feramisco. Mice with the germline mutation of the Asgr-1 hepatocyte asialoglycoprotein receptor were kindly provided by B. Sauer (Stowers Institute for Medical Research, Kansas City, Missouri). Wild-type S. pneumoniae serotype 2 strain D39 and its isogenic NanA mutant were kindly provided by T. Mitchell (University of Glasgow). This research was funded by US National Institutes of Health grants HL-57345 to J.D.M., D.T.L. and N.V. and AI-051796 to V.N. and an American Heart Association Established Investigator Award to V.N. The Howard Hughes Medical Institute provides support to J.D.M.

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Correspondence to Jamey D Marth.

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Grewal, P., Uchiyama, S., Ditto, D. et al. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med 14, 648–655 (2008) doi:10.1038/nm1760

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