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Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo
Matthew J. Flick, … , Edward F. Plow, Jay L. Degen
Matthew J. Flick, … , Edward F. Plow, Jay L. Degen
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1596-1606. https://doi.org/10.1172/JCI20741.
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Article Hematology

Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo

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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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Figure 6

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Cell adhesion to fibrinogen is supported by integrin
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Cell adhesion to fibrinogen is supported by integrin αMβ2, but not the related integrin, αLβ2. (A) Adhesion of HEK293 transfectants expressing either αMβ2, αLβ2, or no β2 integrin (mock transfectants) to microtiter wells coated with either 10 ∝g/ml WT or γ390–396A fibrinogen. (B) Adhesion of αMβ2-expressing HEK293 cells to WT or γ390–396A fibrinogen in the absence or presence of Ab’s against the αM I-domain (M1/70), β2 (IB4), and irrelevant rat anti-mouse IgG. The data shown are means ± SD.

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