Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif.
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 alphaMbeta2 binding motif (Fibgamma390-396A) or the alphaIIbbeta3 platelet integrin-binding motif (FibgammaDelta5), 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 Fibgamma390-396A mice, which retain full clotting function. In contrast, arthritis in FibgammaDelta5 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 Fibgamma390-396A mice with CIA displayed reduced local expression of TNF-alpha, IL-1beta, and IL-6, which suggests that alphaMbeta2-mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-alpha 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 alphaMbeta2-mediated inflammatory processes.
Flick
Matthew J
MJ
Cincinnati Children's Hospital Research Foundation and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
LaJeunesse
Christine M
CM
Talmage
Kathryn E
KE
Witte
David P
DP
Palumbo
Joseph S
JS
Pinkerton
Malinda D
MD
Thornton
Sherry
S
Degen
Jay L
JL
D020816:Amino Acid Motifs; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology; D002417:Cattle; D024043:Collagen Type II / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005337:Fibrin / Q000235:genetics / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D007249:Inflammation; D007596:Joints / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009154:Mutation
D024043:Collagen Type II; D016207:Cytokines; D016177:Macrophage-1 Antigen; D005337:Fibrin; D005340:Fibrinogen