Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif
Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif
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DOI：
10.1172/jci30134
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Degen, Jay L.
中科院分区：
文献类型：
--
作者：
Flick, Matthew J.;LaJeunesse, Christine M.;Degen, Jay L.
关节内纤维蛋白沉积是关节炎的一个显著特征，但纤维蛋白（原）对导致关节损伤的炎症事件的确切作用仍不清楚。为了确定纤维蛋白（原）在关节炎中的重要性，用胶原诱导的关节炎（CIA）攻击缺乏纤维蛋白原（Fib（-））或表达突变形式的纤维蛋白原、缺乏白细胞受体整合素α（M）β（2）结合基序（Fib γ（390- 396 A））或血小板整合素α（IIb）β（3）结合基序（Fib γ（Delta 5））的基因靶向小鼠。与对照组相比，Fib-小鼠表现出较少的受影响关节和降低的疾病严重程度。类似地，在Fib γ（390- 396 A）小鼠中观察到关节炎减轻，其保留完全凝血功能。相比之下，Fib gamma（Delta 5）小鼠的关节炎与对照小鼠的关节炎无法区分。血小板（原）对白细胞向关节的运输不是必需的，但似乎参与白细胞活化事件。患有CIA的Fib（-）和Fib γ（390- 396 A）小鼠显示TNF-α、IL-1 β和IL-6的局部表达降低，这表明α（M）β（2）介导的白细胞与纤维蛋白的接合在促炎介质产生的机制上游。支持这一假设，关节炎疾病驱动旺盛的TNF-α表达并不妨碍纤维蛋白原缺乏。因此，纤维蛋白（原）是关节炎的一个重要但依赖于环境的决定因素，并且将纤维蛋白（原）与关节疾病联系起来的一种机制与α（M）β（2）介导的炎症过程相关联。
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 alpha(M)beta(2) binding motif (Fib gamma(390-396A)) or the alpha(IIb)beta(3) platelet integrin-binding motif (Fib gamma(Delta 5)), 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 Fib gamma(390-396A) mice, which retain full clotting function. In contrast, arthritis in Fib gamma(Delta 5) 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 Fib gamma(390-396A) mice with CIA displayed reduced local expression of TNF-alpha, IL-1 beta, and IL-6, which suggests that alpha(M)beta(2)-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 alpha(M)beta(2)-mediated inflammatory processes.