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SYMPOSIA

Fibrin(ogen)-_Mß₂ Interactions Regulate Leukocyte Function and Innate Immunity In Vivo

Children’s Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229

To whom requests for reprints should be addressed at ¹ Children’s Hospital Research Foundation, Developmental Biology ML7007, CHRF Rm. 2042, 3333 Burnet Ave., Cincinnati, OH 45229–3039. E-mail: degenjl{at}cchmc.org

In addition to its well-characterized role in hemostasis, fibrin(ogen) has been proposed to be a central regulator of the inflammatory response. Multiple in vitro studies have demonstrated that this hemostatic factor can alter leukocyte function, including cell adhesion, migration, cytokine and chemokine expression, degranulation, and other specialized processes. One important link between fibrin(ogen) and leukocyte biology appears to be the integrin receptor _Mß₂/Mac-1, which binds to immobilized fibrin(ogen) and regulates leukocyte activities. Although it is well established that fibrin(ogen) is a ligand for _Mß₂, the precise molecular determinants that govern this interaction are only now becoming clear. A novel line of mice expressing a mutant form of fibrinogen (Fib^390–396A) has revealed that chain residues 390–396 are important for the high-affinity engagement of fibrinogen by _Mß₂ and leukocyte unction in vivo. Fibrinogen ^390–396A failed to support _Mß₂-mediated adhesion of primary neutrophils, monocytes, and macrophages, and mice expressing this fibrinogen variant were found to exhibit a major defect in the host inflammatory response following acute challenges. Most notably, Fib^390–396A mice display a profound impediment in Staphylococcus aureus elimination by leukocytes following intraperitoneal inoculation. These findings have positively established the physiological importance of fibrin(ogen) as a ligand for _Mß₂ and illustrate that the fibrin(ogen) chain residues 390–396 constitute a critical feature of the _Mß₂ binding motif. Finally, the Fib^390–396A mice represent a valuable system for better defining the contribution of fibrin(ogen) to the inflammatory response in the absence of any confounding alteration in clotting function.

Key Words: coagulation • integrin • inflammation • innate immunity

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