Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif
Matthew J. Flick, Christine M. LaJeunesse, Kathryn E. Talmage, David P. Witte, Joseph S. Palumbo, Malinda D. Pinkerton, Sherry Thornton, Jay L. Degen
Matthew J. Flick, Christine M. LaJeunesse, Kathryn E. Talmage, David P. Witte, Joseph S. Palumbo, Malinda D. Pinkerton, Sherry Thornton, Jay L. Degen
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Research Article Inflammation

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 αMβ2 binding motif (Fibγ390–396A) or the αIIbβ3 platelet integrin-binding motif (FibγΔ5), 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 Fibγ390–396A mice, which retain full clotting function. In contrast, arthritis in FibγΔ5 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 Fibγ390–396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that αMβ2-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 αMβ2-mediated inflammatory processes.

Authors

Matthew J. Flick, Christine M. LaJeunesse, Kathryn E. Talmage, David P. Witte, Joseph S. Palumbo, Malinda D. Pinkerton, Sherry Thornton, Jay L. Degen

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Figure 4

Fibrinogen deficiency results in diminished microscopic evidence of disease within knee joints of CIA-challenged mice.

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Fibrinogen deficiency results in diminished microscopic evidence of dise...
Knee joint sections from individual groups of Fib+ and Fib– mice that were either all male (n = 22 mice, 44 knees per genotype) or all female (n = 13 mice, 26 knees per genotype) mice were processed for histological evaluation on day 40 of the CIA protocol. (A) Composite histopathology index (the sum of scores for individual disease parameters) for each Fib– and Fib+ mouse immunized with CII. Symbols denote values for individual mice; bars denote median values. P < 0.002, P < 0.005 between groups in male and female mice, respectively; Mann-Whitney U test. (B) Scores for each of the knee histology evaluation parameters. Every disease parameter evaluated was significantly reduced in Fib– relative to Fib+ CII-immunized mice. Data are mean ± SEM. *P < 0.05, **P < 0.0005, ***P < 0.0001, Student’s t test.