Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b
Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b
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DOI：
10.1074/jbc.ra118.006724
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发表时间：
2019-05-31
影响因子：
4.8
通讯作者：
Corry, David B.
中科院分区：
文献类型：
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作者：
Landers, Cameron T.;Tung, Hui-Ying;Corry, David B.
蛋白酶是过敏性气道疾病和先天性抗真菌免疫的重要驱动因素，部分原因是它们能够将凝血因子纤维蛋白原（FBG）切割成纤维蛋白原切割产物（FCP），FCP通过Toll样受体4（TLR 4）发出信号。然而，FCPs参与TLR 4的机制仍然未知。在这里，我们表明，蛋白酶从Aspergillus melleus（PAM）和其他过敏性生物体迅速水解FBG，产生相对较少的FCPs，驱动不同的抗真菌机制，通过TLR 4。功能性FCPs，称为隐因子，其特征在于FBG链的快速丢失，并基本保留了和链，包括结合整合素Mac-1（CD 11b/CD 18）的链序列（Fib 390 -396）。PAM衍生的隐因子可以从多个FBG结构域产生，并且隐因子在体外诱导真菌抑制和在体内诱导先天性过敏性气道疾病的能力强烈依赖于Mac-1和FBG的Mac-1结合结构域（Fib 390 -396）。我们的研究结果阐明了蛋白酶激活免疫反应的基本概念，并首次将Mac-1，隐因子和TLR 4与先天性抗真菌免疫和过敏性气道疾病联系起来。
Proteinases are essential drivers of allergic airway disease and innate antifungal immunity in part through their ability cleave the clotting factor fibrinogen (FBG) into fibrinogen cleavage products (FCPs) that signal through Toll-like receptor 4 (TLR4). However, the mechanism by which FCPs engage TLR4 remains unknown. Here, we show that the proteinases from Aspergillus melleus (PAM) and other allergenic organisms rapidly hydrolyze FBG to yield relatively few FCPs that drive distinct antifungal mechanisms through TLR4. Functional FCPs, termed cryptokines, were characterized by rapid loss of the FBG chain with substantial preservation of the and chains, including a chain sequence (Fib390-396) that binds the integrin Mac-1 (CD11b/CD18). PAM-derived cryptokines could be generated from multiple FBG domains, and the ability of cryptokines to induce fungistasis in vitro and innate allergic airway disease in vivo strongly depended on both Mac-1 and the Mac-1-binding domain of FBG (Fib390-396). Our findings illustrate the essential concept of proteinase-activated immune responses and for the first time link Mac-1, cryptokines, and TLR4 to innate antifungal immunity and allergic airway disease.