Platelet-driven monocyte activation promotes hypoxic thromboinflammation through the HIF-1α-NLRP3-EGR-1 axis

Area of Science:

• * Cardiovascular Biology
• * Inflammation Research
• * Thrombosis and Hemostasis

Background:

• * Hypoxia is a known risk factor for thromboembolism, particularly deep vein thrombosis (DVT).
• * The interplay between hypoxia, sterile inflammation, and thrombosis is complex and not fully elucidated.
• * The NLRP3 inflammasome and HIF-1α are implicated in inflammatory processes and thrombosis.

Purpose of the Study:

• * To investigate the mechanistic link between hypoxia, sterile inflammation, and thrombosis.
• * To identify key molecular players and cellular interactions driving hypoxia-induced DVT.
• * To evaluate the translational potential of identified targets in human DVT at high altitudes.

Main Methods:

• * Integrated in vitro cell lines, ex vivo human primary blood mononuclear cells (hPBMCs), in vivo animal models, and human patient studies.
• * Investigated monocyte adhesion, inflammasome activation, and coagulation factor expression under hypoxic conditions.
• * Utilized pharmacological inhibitors and siRNAs to assess the therapeutic potential of targeted molecules.

Main Results:

• * Hypoxia increases monocyte adhesion to endothelial cells via CD11a/CD18 and F11R.
• * Identified the HIF-1α-NLRP3-Egr1-TF/FVII axis as crucial for sterile inflammation-induced coagulation.
• * Confirmed elevated levels of HIF-1α, NLRP3, Egr1, and TF/FVII in high-altitude DVT patients.

Conclusions:

• * The HIF-1α-NLRP3-Egr1-TF/FVII axis is a key mediator of hypoxia-induced thromboinflammation.
• * Targeting this axis can potentially reverse hypoxia-driven prothrombotic processes.
• * This pathway represents a promising therapeutic target for preventing and treating DVT in hypoxic conditions.