Fibrin(ogen)-α_Mβ₂Interactions Regulate Leukocyte Function and Innate Immunity In Vivo

Abstract

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 alpha(M)beta(2)/Mac-1, which binds to immobilized fibrin(ogen) and regulates leukocyte activities. Although it is well established that fibrin(ogen) is a ligand for alpha(M)beta(2), 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 gamma(390-396A)) has revealed that gamma chain residues 390-396 are important for the high-affinity engagement of fibrinogen by alpha(M)beta(2) and leukocyte function in vivo. Fibrinogen gamma(390-396A) failed to support alpha(M)beta(2)-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 gamma(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 alpha(M)beta(2) and illustrate that the fibrin(ogen) gamma chain residues 390-396 constitute a critical feature of the alpha(M)beta(2) binding motif. Finally, the Fib gamma(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.

Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion

“…by guest www.bloodjournal.org From to support increased inflammatory cell adhesion, migration, and cytokine production relative to monomeric fibrinogen. [28][29][30] Interestingly, the common V34L polymorphism in the fXIIIA gene, which is associated with more rapid fXIII activation, correlates with higher levels of the proinflammatory cytokine IL-6. 31 Indeed, the observed diminution of CIA severity in fXIIIA 2/2 mice reported here is in-line with previous studies indicating that fibrinogen-deficient mice develop diminished CIA with a corresponding reduction in local proinflammatory cytokine expression.…”

Dynamics of podosome stiffness revealed by atomic force microscopy

“…S1A). Because fibrinogen is mostly found at inflamed sites, we decided to focus on this protein (14). We started AFM experiments with formaldehyde-fixed macrophages, which allowed the use of correlative fluorescence microscopy.…”

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

“…For Tg197 transgenic mice, the following scoring criteria were used: inflammation (range, 0-3), subluxation (range, 0-3), bone loss (range, 0-3), articular erosion (range, 0-2), synovial hyperplasia (range, 0-3), and pannus (range, 0-1). Representative sections were also immunostained for fibrin deposition using a rabbit anti-mouse fibrin polyclonal serum (44) and peroxidase/DAB development system. Analysis of percent intact articular surface cartilage in knee joint sections was performed using morphometric image analysis software (Axiovision Release 4.5; Carl Zeiss Microimaging Inc.).…”