title: Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo.
abstract: The leukocyte integrin alpha(M)beta(2)/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)-alpha(M)beta(2) interaction in vivo, gene-targeted mice were generated in which the alpha(M)beta(2)-binding motif within the fibrinogen gamma chain (N(390)RLSIGE(396)) was converted to a series of alanine residues. Mice carrying the Fibgamma(390-396A) 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 alpha(M)beta(2)-mediated adhesion of primary neutrophils, macrophages, and alpha(M)beta(2)-expressing cell lines. The elimination of the alpha(M)beta(2)-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 alpha(M)beta(2), 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.affiliation: Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: XinLi
authors.initials: X
authors.lastname: Du
authors.forename: David P
authors.initials: DP
authors.lastname: Witte
authors.forename: Markéta
authors.initials: M
authors.lastname: Jirousková
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Soloviev
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Busuttil
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism; D005337:Fibrin / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed
chemical_list: D016177:Macrophage-1 Antigen; D005337:Fibrin; D005340:Fibrinogen