Fibrin(ogen)-alpha M beta 2 interactions regulate leukocyte function and innate immunity in vivo

Area of Science:

• Immunology
• Hematology
• Molecular Biology

Background:

• Fibrinogen, known for its role in hemostasis, also influences inflammatory responses.
• Leukocyte function, including adhesion and migration, is modulated by fibrinogen.
• The integrin receptor alpha(M)beta(2) (Mac-1) binds fibrinogen, mediating leukocyte activities.

Purpose of the Study:

• To elucidate the molecular determinants of fibrinogen binding to alpha(M)beta(2).
• To investigate the in vivo role of specific fibrinogen gamma chain residues in leukocyte function and inflammation.

Main Methods:

• Generation and analysis of mice expressing a mutant fibrinogen (Fib gamma(390-396A)).
• Assessment of alpha(M)beta(2)-mediated adhesion of neutrophils, monocytes, and macrophages.
• Evaluation of inflammatory response and bacterial clearance in mutant mice following acute challenges.

Main Results:

• Fibrinogen gamma chain residues 390-396 are critical for high-affinity alpha(M)beta(2) engagement.
• Fib gamma(390-396A) mutant fibrinogen failed to support alpha(M)beta(2)-mediated leukocyte adhesion.
• Mice expressing Fib gamma(390-396A) exhibited impaired inflammatory responses and reduced Staphylococcus aureus clearance.

Conclusions:

• Fibrinogen is a key ligand for alpha(M)beta(2), essential for leukocyte function in vivo.
• Fibrinogen gamma chain residues 390-396 are a critical component of the alpha(M)beta(2) binding motif.
• Fib gamma(390-396A) mice provide a model to study fibrinogen's role in inflammation without affecting hemostasis.