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

Abstract

Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib -) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin α M β 2 binding motif (Fibγ 390-396A ) or the α IIb β 3 platelet integrin-binding motif (Fibγ Δ5 ), were challenged with collagen-induced arthritis (CIA). Fib -mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ 390-396A mice, which retain full clotting function. In contrast, arthritis in Fibγ Δ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib -and Fibγ 390-396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that α M β 2 -mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to α M β 2 -mediated inflammatory processes.

Factor XIII activity mediates red blood cell retention in venous thrombi

“…However, Fibγ 390-396A mice have defective clearance of Staphylococcus aureus (4) and are protected against autoinflammatory disorders (5)(6)(7)(8)(9). These effects are thought to stem from the lack of fibrin-driven leukocyte responses during inflammation.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…In addition, fibrin can enhance inflammation and provides a matrix for cell adhesion and migration (9). A role for fibrin in arthritis development via ␣M␤2-dependent leukocyte activation and changes in the inflammation status is supported by the reduction in collagen-induced arthritis (CIA) disease severity in mice lacking either fibrinogen or the leukocyte receptor integrin ␣M␤2-binding motif for fibrinogen (14).…”

Tissue factor promotes activation of coagulation and inflammation in a mouse model of sickle cell disease

“…It has been demonstrated that leukocyte engagement of fibrin via Mac-1 (␣ M ␤ 2 ) contributes to local inflammation by activating leukocytes and increasing the expression of proinflammatory cytokines. 41,42 Furthermore, the E1 degradation fragment of fibrin has been shown to facilitate neutrophil infiltration into infarcted tissues after ischemia-reperfusion injury. 43 However, in contrast to the beneficial effects of blocking TF observed in this study, fibrinogen deficiency was associated with increased mortality in a milder mouse model of SCD (SAD mice).…”