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Inflammasome-Independent Mechanism of NLRP3 Is Critical for Platelet GPIb-IX Function and Thrombosis.
Chen, Xiaoyan; Li, Jingke; Liu, Pu; Zhou, Yangfan; Zhang, Tongtong; Li, Li; Shi, Jingqi; Deng, Xin; Sheng, Yilin; Chen, Wei; Wang, Di; Hu, Hu.
Afiliación
  • Chen X; Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Li J; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, People's Republic of China.
  • Liu P; Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Zhou Y; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, People's Republic of China.
  • Zhang T; Department of Pathology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Li L; Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Shi J; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, People's Republic of China.
  • Deng X; Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Sheng Y; Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Chen W; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, People's Republic of China.
  • Wang D; Department of Pathology and Pathophysiology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
  • Hu H; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, People's Republic of China.
Thromb Haemost ; 2024 Apr 23.
Article en En | MEDLINE | ID: mdl-38325399
ABSTRACT

INTRODUCTION:

Platelets link thrombosis and inflammation, but how platelets handle the endogenous intraplatelet inflammatory machinery is less well understood. NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) is the central component of the interleukin (IL)-1-producing inflammasome. Elucidating the cell type-specific mechanism of NLRP3 in platelets may improve our understanding of thrombotic diseases.

METHODS:

Ferric chloride-induced mesenteric arteriole thrombosis models, tail bleeding models, and microfluidic whole-blood perfusion were used to study thrombosis and hemostasis. Additionally, we utilized aggregometry, flow cytometry, immunoprecipitation, and western blotting to investigate glycoprotein (GP)Ib-IX-mediated platelet function and signaling.

RESULTS:

NLRP3-/- mice exhibited severely impaired thrombosis and hemostasis, whereas apoptosis-associated speck-like protein containing a CARD (ASC)-/-, caspase-1-/-, and Nlrp3 A350V/+ CrePF4 mice did not exhibit such changes. NLRP3-/- platelets exhibited reduced adhesion to injured vessel walls and collagen and impaired von Willebrand factor (vWF)-dependent translocation and rolling behavior. NLRP3 deficiency decreased botrocetin-induced platelet aggregation and the phosphorylation of key signaling molecules in the GPIb-IX pathway. Mechanistically, decreased cAMP/PKA activity led to reduced phosphorylation of NLRP3, thereby enabling the interaction between NLRP3 and filamin A. This interaction accelerated the dissociation of filamin A from GPIbα, which allowed a 14-3-3ζ-dependent increase in GPIb-IX affinity to vWF. Finally, platelet NLRP3 was found to largely regulate thrombotic disease models, such as models of stroke and deep vein thrombosis.

CONCLUSION:

NLRP3 promoted the function of the major platelet adhesion receptor GPIb-IX without involving NLRP3 inflammasome assembly or IL-1ß production.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Thromb Haemost Año: 2024 Tipo del documento: Article Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Thromb Haemost Año: 2024 Tipo del documento: Article Pais de publicación: Alemania