Abstract
The leukocyte integrin αMβ2/Mac-1
appears to support the inflammatory response through multiple ligands, but local
engagement of fibrin(ogen) may be particularly important for leukocyte function.
To define the biological significance of
fibrin(ogen)-αMβ2 interaction
in vivo, gene-targeted mice were generated in which the
αMβ2-binding motif within the
fibrinogen γ chain (N390RLSIGE396) was
converted to a series of alanine residues. Mice carrying the Fibγ390–396A allele maintained normal levels of fibrinogen, retained normal clotting
function, supported platelet aggregation, and never developed spontaneous
hemorrhagic events. However, the mutant fibrinogen failed to support
αMβ2-mediated adhesion of
primary neutrophils, macrophages, and
αMβ2-expressing cell lines.
The elimination of the
αMβ2-binding motif on fibrin(ogen)
severely compromised the inflammatory response in vivo as evidenced by a
dramatic impediment in leukocyte clearance of Staphylococcus
aureus inoculated into the peritoneal cavity. This defect in bacterial
clearance was due not to diminished leukocyte trafficking but rather to a
failure to fully implement antimicrobial functions. These studies definitively
demonstrate that fibrin(ogen) is a physiologically relevant ligand for
αMβ2, integrin engagement of
fibrin(ogen) is critical to leukocyte function and innate immunity in vivo, and
the biological importance of fibrinogen in regulating the inflammatory response
can be appreciated outside of any alteration in clotting function.
Authors
Matthew J. Flick, XinLi Du, David P. Witte, Markéta Jiroušková, Dmitry A. Soloviev, Steven J. Busuttil, Edward F. Plow, Jay L. Degen
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