Platelet Glycoprotein Ibα Cytoplasmic Tail Exacerbates Thrombosis During Bacterial Sepsis

• Published in: International journal of molecular sciences 2024-11, Vol.25 (21), p.11548
• Main Authors: Xia, Yue, Sun, Chenglin, Zhou, Kangxi, Shen, Jie, Li, Jiaojiao, Huang, Qiuxia, Du, Jiahao, Zhang, Sai, Sun, Kang, Hu, Renping, Yan, Rong, Dai, Kesheng
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; Bacterial infections; Blood clot; Blood platelets; Blood Platelets - metabolism; Development and progression; Disease Models, Animal; Escherichia coli; Glycoproteins; Health aspects; Inflammation; Kupffer Cells - metabolism; Ligands; Male; Medical prognosis; Mice; Mice, Inbred C57BL; Mortality; Multiple organ dysfunction syndrome; Peptides; Phagocytosis; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex - genetics; Platelet Glycoprotein GPIb-IX Complex - metabolism; Protein Kinase C - metabolism; Sepsis; Sepsis - complications; Sepsis - metabolism; Sepsis - microbiology; Staphylococcal Infections - complications; Staphylococcal Infections - metabolism; Staphylococcal Infections - microbiology; Staphylococcus aureus - pathogenicity; Staphylococcus infections; Thrombocytopenia; Thrombosis; Thrombosis - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252111548

Septic patients, coupling severe disseminated intravascular coagulation (DIC) and thrombocytopenia, have poor prognoses and higher mortality. The platelet glycoprotein Ibα (GPIbα) is involved in thrombosis, hemostasis, and inflammation response. However, it remains unclear whether the GPIbα cytoplasmic tail regulates sepsis-mediated platelet activation and inflammation, especially in Staphylococcus aureus ( ) and Escherichia coli ( ) infections. Using a mouse model of -induced bacteremia, we found that both 10 amino acids of GPIbα C-terminal sequence deficiency and pharmacologic inhibition of protein kinase C (PKC) alleviated pathogenesis by diminishing platelet activation and aggregate formation. Furthermore, the GPIbα cytoplasmic tail promoted the phagocytosis of platelets by Kupffer cells in vivo. The genetically deficient GPIbα cytoplasmic tail also downregulated inflammatory cytokines and reduced liver damage, ultimately improving the survival rate of the septic mice. Our results illustrate that the platelet GPIbα cytoplasmic domain exacerbates excessive platelet activation and inflammation associated with sepsis through a PKC-dependent pathway. Thus, our findings provide insights for the development of effective therapeutic strategies using PKC inhibitor treatment against bacterial infection.