Adiponectin Assists Thrombopoietic Agents in ITP Treatment by Enhancing Myosin-9/Rab6A-Mediated Trafficking of c-Mpl in MKs.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by accelerated platelet destruction and defective platelet production. The thrombopoietin (TPO)-activated c-Mpl signaling pathway has been proven to promote megakaryocyte differentiation and platelet production and thus has significant value in the clinical treatment of ITP. However, individual differences and unsustainable responses limit the clinical application of c-Mpl agonists. The cell membrane distribution of c-Mpl is crucial for the cell response to c-Mpl agonists. In the present study, this is observed that the distribution of c-Mpl on the megakaryocyte membrane is significantly reduced in ITP patients. The reduction is more severe in refractory patients. Then, this is verified that the membrane trafficking of c-Mpl is mediated by the Myosin-9/Rab6A complex, and demonstrates that the stability of this complex depends on Rab6A-GTPase. Furthermore, this is found that adiponectin promotes the membrane localization of c-Mpl by increasing the expression of Rab6A GEFs. Finally, this is revealed that adiponectin can assist thrombopoietic agents in the treatment of ITP mice. The results clarify the c-Mpl distribution defects in the cell membrane and the corresponding c-Mpl membrane transport mechanisms in megakaryocytes of ITP, providing new insights to improve the clinical efficacy of thrombopoietic agents for ITP patients.