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

Abstract

Binding of aged, desialylated platelets to the Ashwell-Morell receptor induces hepatic expression of the cytokine thrombopoietin via JAK2-STAT3 signaling, providing a feedback mechanism to control platelet production. 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.