Platelet ITGA2B inhibits caspase-8 and Rip3/Mlkl-dependent platelet death though PTPN6 during sepsis

Jiang Jiang; Wei Li; Lu Zhou; Dengping Liu; Yuanyuan Wang; Jianzhong An; Shigang Qiao; Zhanli Xie

doi:10.1016/j.isci.2023.107414

Platelet ITGA2B inhibits caspase-8 and Rip3/Mlkl-dependent platelet death though PTPN6 during sepsis

iScience. 2023 Jul 19;26(8):107414. doi: 10.1016/j.isci.2023.107414. eCollection 2023 Aug 18.

Authors

Jiang Jiang¹, Wei Li², Lu Zhou³, Dengping Liu⁴, Yuanyuan Wang⁵, Jianzhong An², Shigang Qiao^{2

6}, Zhanli Xie²

Affiliations

¹ Department of Nuclear Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China.
² Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China.
³ Hematology Department, Affiliated Hospital of Nantong University, Nantong, China.
⁴ Suzhou Center for Disease Control and Prevention, Suzhou, China.
⁵ Department of Intensive Care Unit, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China.
⁶ Faculty of Anesthesiology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, China.

Abstract

Platelets play an important role in the pathogenesis of sepsis and platelet transfusion is a therapeutic option for sepsis patients, although the exact mechanisms have not been elucidated so far. ITGA2B encodes the αIIb protein in platelets, and its upregulation in sepsis is associated with increased mortality rate. Here, we generated a Itga2b (Q887X) knockin mouse, which significantly reduced ITGA2B expression of platelet and megakaryocyte. The decrease of ITGA2B level aggravated the death of septic mice. We analyzed the transcriptomic profiles of the platelets using RNA sequencing. Our findings suggest that ITGA2B upregulates PTPN6 in megakaryocytes via the transcription factors Nfkb1 and Rel. Furthermore, PTPN6 inhibits platelet apoptosis and necroptosis during sepsis by targeting the Ripk1/Ripk3/Mlkl and caspase-8 pathways. This prevents Kupffer cells from rapidly clearing activated platelets, and eventually maintains vascular integrity during sepsis. Our findings indicate a new function of ITGA2B in the regulation of platelet death during sepsis.

Keywords: Biological sciences; Immunology; Natural sciences; Pathophysiology; Physiology.