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Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα
Yunmei Wang1, Huiyun Gao1, Can Shi1
1Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart &Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106, USA.
Nature Communications
|May 31, 2017
Summary
Leukocyte Mac-1 and platelet GPIbα interaction is crucial for thrombosis. Targeting this pathway may offer anti-thrombotic therapies with a lower risk of bleeding.
Area of Science:
- Biomedical research
- Hematology
- Immunology
Background:
- Inflammation and thrombosis are interconnected in various diseases.
- Leukocyte integrin Mac-1 (CD11b/CD18) mediates leukocyte recruitment and platelet interaction.
- The specific role of Mac-1 in thrombosis remained unclear.
Purpose of the Study:
- To define the role of Mac-1 in thrombosis.
- To investigate the Mac-1:GPIbα interaction in thrombosis.
- To explore the therapeutic potential of targeting this interaction.
Main Methods:
- Utilized Mac-1 deficient (Mac-1-/-) mice and mice with mutated Mac-1 binding sites.
- Assessed thrombosis following carotid artery and cremaster microvascular injury.
- Employed adoptive leukocyte transfer and genetic manipulation of Foxp1.
- Investigated antibody and small-molecule inhibitors targeting Mac-1:GPIbα.
Main Results:
- Mac-1 deficiency or mutated binding sites delayed thrombosis after injury.
- Haemostasis parameters were unaffected in Mac-1 deficient mice.
- Leukocyte Mac-1 is essential for thrombosis, independent of primary haemostasis.
- Foxp1 regulation by Mac-1 influences thrombosis.
- Targeting Mac-1:GPIbα inhibited thrombosis.
Conclusions:
- Identified a novel pathway for thrombosis involving leukocyte Mac-1 and platelet GPIbα.
- This interaction is critical for thrombus formation after vascular injury.
- Targeting the Mac-1:GPIbα interaction presents a promising anti-thrombotic strategy with potentially reduced bleeding risks.
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