Current View on the Molecular Mechanisms Underlying Fibrin(ogen)-Dependent Inflammation.

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Fibrinogen plays a key role in inflammation through leukocyte-endothelial cell interactions.
• Two mechanisms, involving Mac-1/ICAM-1 and E1 fragment/VE-cadherin, have been proposed for fibrinogen-mediated leukocyte transmigration.
• The inhibitory role of the β15-42 fragment has been attributed to interference with E1-VE-cadherin interactions or Fyn kinase signaling.

Approach:

• Investigated the molecular mechanisms of fibrinogen-dependent leukocyte transmigration.
• Evaluated the efficacy of the β15-42 fragment in inhibiting E1- or fibrin-VE-cadherin interactions.
• Identified a novel pathway involving the very-low-density lipoprotein (VLDL) receptor and Fyn kinase.

Key Points:

• The β15-42 fragment's inhibitory function is not due to blocking E1-VE-cadherin interactions.
• Fibrin directly interacts with the VLDL receptor, initiating a signaling cascade.
• This VLDL receptor pathway promotes leukocyte transmigration via Fyn kinase inhibition.

Conclusions:

• A novel VLDL receptor-dependent pathway contributes significantly to fibrin-dependent inflammation.
• This pathway involves fibrin binding to the VLDL receptor, leading to Fyn kinase inhibition and leukocyte transmigration.
• The β15-42 fragment inhibits this pathway through interaction with a distinct endothelial receptor.