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- Title
A targetable pathway in neutrophils mitigates both arterial and venous thrombosis.
- Authors
Nayak, Lalitha; Sweet, David R.; Thomas, Asha; Lapping, Stephanie D.; Kalikasingh, Kenneth; Madera, Annmarie; Vinayachandran, Vinesh; Padmanabhan, Roshan; Vasudevan, Neelakantan T.; Myers, Jay T.; Huang, Alex Y.; Schmaier, Alvin; Mackman, Nigel; Liao, Xudong; Maiseyeu, Andrei; Jain, Mukesh K.
- Abstract
Arterial and venous thrombosis constitutes a major source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that arterial and venous thrombosis can occur in the same populations, suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, antithrombotic therapies targeting the immune system for therapeutics gain are lacking. Here, we show that neutrophils are key effectors of both arterial and venous thrombosis and can be targeted through immunoregulatory nanoparticles. Using antiphospholipid antibody syndrome (APS) as a model for arterial and venous thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation through genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils clustered P-selectin glycoprotein ligand 1 (PSGL-1) by cortical actin remodeling, thereby increasing adhesion potential at sites of thrombosis. Targeting clustered PSGL-1 using nanoparticles attenuated neutrophil-mediated thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutrophils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis. Thwarting thrombosis: Arterial and venous thrombosis can affect nearly every organ system and likely share common drivers. Thus, identifying those common drivers may reveal a therapeutic target to prevent disease caused by thrombosis. Here, Nayak et al. used antiphospholipid antibody syndrome (APS) as a model to identify neutrophils as a driver of immunothrombosis. Neutrophil-specific deletion of Krüppel-like factor 2, a transcription factor regulating neutrophil activation, worsened disease in mice by driving neutrophil activation. In contrast, targeting of P-selectin glycoprotein ligand 1 (PSGL-1) on activated neutrophils attenuated APS symptoms in mice by preventing downstream adhesion and thrombosis development. Together, the authors show that neutrophils, and, more specifically, PSGL-1, may be useful clinical targets for APS and other causes of immunothrombosis.
- Subjects
VENOUS thrombosis; PHOSPHOLIPID antibodies; KRUPPEL-like factors; CARDIOVASCULAR system; NEUTROPHILS; TRANSCRIPTION factors; ANTIPHOSPHOLIPID syndrome
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 660, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abj7465