Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia
Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia
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Akt 介导的血小板凋亡及其对免疫性血小板减少症的治疗意义
DOI：
10.1073/pnas.1808217115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Dai, Kesheng
中科院分区：
文献类型：
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作者：
Chen, Mengxing;Yan, Rong;Dai, Kesheng
免疫性血小板减少症（ITP）是一种自身免疫性疾病，其特征是血小板计数低，可导致致命性出血。伴有抗血小板糖蛋白（GP）Ib - IX自身抗体的ITP患者对常规治疗似乎有抵抗性，其机制仍不清楚。在此我们表明，伴有抗GPIbα自身抗体的ITP患者的血小板会发生凋亡。与这些发现一致的是，抗GPIbα单克隆抗体AN51和SZ2在体外可诱导血小板凋亡。我们证明抗GPIbα抗体结合可激活Akt，Akt通过激活磷酸二酯酶（PDE3A）以及PDE3A介导的PKA抑制来引发血小板凋亡。Akt的基因敲除或化学抑制，或者Akt信号通路的阻断，可消除抗GPIbα抗体诱导的血小板凋亡。我们进一步证明，抗体结合的血小板在体内以一种依赖凋亡的方式被清除。凋亡血小板上的磷脂酰丝氨酸（PS）暴露导致肝脏中的巨噬细胞对血小板进行吞噬。值得注意的是，Akt的抑制或基因敲除、Akt调节的凋亡信号通路的阻断或者PS暴露的阻断，可保护血小板不被清除。因此，我们的研究结果揭示了伴有抗GPIbα自身抗体的ITP的致病机制，更重要的是，为自身抗体或其他致病因素导致的血小板减少症提出了治疗策略。
Significance Immune thrombocytopenia (ITP) patients with antiplatelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments; however, the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIbα autoantibodies. We demonstrate that anti-GPIbα antibody binding activates Akt, which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Phosphatidylserine (PS) exposure results in phagocytosis of anti-GPIbα antibody-bound platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling or blockage of PS exposure rescues the platelets from clearance. Therefore, our findings reveal pathogenic mechanisms of ITP with anti-GPIbα autoantibodies and, more importantly, suggest therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors. 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-GPIbα autoantibodies. Consistent with these findings, the anti-GPIbα monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIbα 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-GPIbα 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-GPIbα autoantibodies and, more importantly, suggest therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.