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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia
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Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia

机译：Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia

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Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with antiplatelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIba autoantibodies. Consistent with these findings, the anti-GPIba monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate thatanti-GPIba antibody binding activates Akt, which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIba antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal pathogenic mechanisms of ITP with anti-GPIba autoantibodies and, more importantly, suggest therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.

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