Details

Autor(en) / Beteiligte

• Chen, Mengxing
• Yan, Rong
• Zhou, Kangxi
• Li, Xiaodong
• Zhang, Yang
• Liu, Chunliang
• Jiang, Mengxiao
• Ye, Honglei
• Meng, Xingjun
• Pang, Ningbo
• Zhao, Lili
• Liu, Jun
• Xiao, Weiling
• Hu, Renping
• Cui, Qingya
• Zhong, Wei
• Zhao, Yunxiao
• Zhu, Mingqing
• Lin, Anning
• Ruan, Changgeng
• Dai, Kesheng

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2018-11, Vol.115 (45), p.E10682-E10691

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.