Fibrin(ogen)αMβ2 interactions regulate leukocyte function and innate immunity in vivo
Fibrin(ogen)αMβ2 interactions regulate leukocyte function and innate immunity in vivo
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DOI：
10.1177/153537020422901104
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发表时间：
2004-12-01
影响因子：
3.2
通讯作者：
Degen, JL
中科院分区：
文献类型：
--
作者：
Flick, MJ;Du, XL;Degen, JL
除了在止血方面的作用外，纤维蛋白(原)也被认为是炎症反应的中心调节因子。多项体外研究表明，这种止血因子可以改变白细胞的功能，包括细胞黏附、迁移、细胞因子和趋化因子的表达、脱颗粒等特殊过程。纤维蛋白原与白细胞生物学之间的一个重要联系似乎是整合素受体α(M)β(2)/Mac-1，它与固定的纤维蛋白原结合并调节白细胞的活动。虽然纤维蛋白(原)是α(M)β(2)的配基是公认的，但支配这种相互作用的确切分子决定因素直到现在才变得清晰。一种新的表达突变形式的纤维蛋白原(FibGamma(390-396A))的小鼠已经揭示，伽马链残基390-396对于体内α(M)β(2)与纤维蛋白原的高亲和力结合和白细胞功能是重要的。纤维蛋白原γ(390-396A)不支持α(M)β(2)介导的原代中性粒细胞、单核细胞和巨噬细胞的黏附，表达这种纤维蛋白原变体的小鼠被发现在急性挑战后的宿主炎症反应中表现出主要缺陷。最值得注意的是，FibGamma(390-396A)小鼠在腹膜内接种后表现出严重的白细胞清除金黄色葡萄球菌的障碍。这些发现肯定了纤维蛋白(原)作为α(M)β(2)配体的生理重要性，并说明纤维蛋白(原)伽马链残基390-396构成了α(M)β(2)结合基序的关键特征。最后，FibGamma(390-396A)小鼠是一个有价值的系统，可以在凝血功能没有任何混淆变化的情况下，更好地确定纤维蛋白(原)对炎症反应的贡献。
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 (Fibgamma(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 unction 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, Fibgamma(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 Fibgamma(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.