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

Authors :
Jiang Jiang
Wei Li
Lu Zhou
Dengping Liu
Yuanyuan Wang
Jianzhong An
Shigang Qiao
Zhanli Xie
Source :
iScience, Vol 26, Iss 8, Pp 107414- (2023)
Publication Year :
2023
Publisher :
Elsevier, 2023.

Abstract

Summary: 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.

Details

Language :
English
ISSN :
25890042
Volume :
26
Issue :
8
Database :
Directory of Open Access Journals
Journal :
iScience
Publication Type :
Academic Journal
Accession number :
edsdoj.26e226f30f174031a14f46d4a01ba476
Document Type :
article
Full Text :
https://doi.org/10.1016/j.isci.2023.107414