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The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling

Abstract

The hepatic Ashwell-Morell receptor (AMR) can bind and remove desialylated platelets. Here we demonstrate that platelets become desialylated as they circulate and age in blood. Binding of desialylated platelets to the AMR induces hepatic expression of thrombopoietin (TPO) mRNA and protein, thereby regulating platelet production. Endocytic AMR controls TPO expression through Janus kinase 2 (JAK2) and the acute phase response signal transducer and activator of transcription 3 (STAT3) in vivo and in vitro. Recognition of this newly identified physiological feedback mechanism illuminates the pathophysiology of platelet diseases, such as essential thrombocythemia and immune thrombocytopenia, and contributes to an understanding of the mechanisms of thrombocytopenia observed with JAK1/2 inhibition.

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Figure 1: The Ashwell-Morell receptor regulates TPO homeostasis.
Figure 2: JAK2-STAT3 signaling regulates hepatic TPO mRNA and protein expression in vivo.
Figure 3: JAK2-STAT3 signaling regulates TPO mRNA expression in vitro.
Figure 4: Injection of exogenously desialylated platelets stimulates hepatic TPO mRNA expression, TPO release and platelet production in mice.
Figure 5: Antibody-mediated thrombocytopenia does not stimulate liver TPO mRNA expression.

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Acknowledgements

We thank M. Adelman, S. Yang and R. Abdu for technical assistance. We are grateful to M. Sola-Visner and T. Stossel (Harvard Medical School) for helpful discussions and to W. Tong (University of Pennsylvania), for the anti-Mpl antibody. This work was supported by US National Institutes of Health grants R01 HL089224, P01 HL059561 and the Program of Excellence in Glycosciences (P01 HL107146). We thank F. Maigen for statistical guidance and expertise. We dedicate this work to the memory of Gilbert Ashwell (1916–2014) and Anatol Morell (1913–2009).

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R.G. designed and performed research, collected, analyzed and interpreted results, and assisted with writing the manuscript. A.J.B. analyzed and interpreted results. K.L. performed splenectomy. G.V. interpreted results. J.H.H. analyzed and interpreted results and assisted with writing the manuscript. H.F. and K.M.H. designed research, analyzed and interpreted results, and wrote the manuscript.

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Correspondence to Hervé Falet or Karin M Hoffmeister.

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Grozovsky, R., Begonja, A., Liu, K. et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 21, 47–54 (2015). https://doi.org/10.1038/nm.3770

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