Ressler Steven J, Dang Truong D, Wu Samuel M, Tse Dennis Y, Gilbert Brian E, Vyakarnam Annapurna, Yang Feng, Schauer Isaiah G, Barron David A, Rowley David R
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Department of Ophthalmology, Baylor College of Medicine, Houston, Texas.
Am J Pathol. 2014 Nov;184(11):2951-64. doi: 10.1016/j.ajpath.2014.07.013. Epub 2014 Sep 16.
WFDC1/ps20 is a whey acidic protein four-disulfide core member that exhibits diverse growth and immune-associated functions in vitro. In vivo functions are unknown, although WFDC1 is lower in reactive stroma. A Wfdc1-null mouse was generated to assess core functions. Wfdc1-null mice exhibited normal developmental and adult phenotypes. However, homeostasis challenges affected inflammatory and repair processes. Wfdc1-null mice infected with influenza A exhibited 2.75-log-fold lower viral titer relative to control mice. Wfdc1-null infected lungs exhibited elevated macrophages and deposition of osteopontin, a potent macrophage chemokine. In wounding studies, Wfdc1-null mice exhibited an elevated rate of skin closure, and this too was associated with elevated deposition of osteopontin and macrophage recruitment. Wfdc1-null fibroblasts exhibited impaired spheroid formation, elevated adhesion to fibronectin, and an increased rate of wound closure in vitro. This was reversed by neutralizing antibody to osteopontin. Osteopontin mRNA and cleaved protein was up-regulated in Wfdc1-null cells treated with lipopolysaccharide or polyinosinic-polycytidylic acid coordinate with constitutively active matrix metallopeptidase-9 (MMP-9), a protease that cleaves osteopontin. These data suggest that WFDC1/ps20 modulates core host response mechanisms, in part, via regulation of osteopontin and MMP-9 activity. Release from WFDC1 regulation is likely a key component of inflammatory and repair response mechanisms, and involves the processing of elevated osteopontin by activated MMP-9, and subsequent macrophage recruitment.
WFDC1/ps20是一种乳清酸性蛋白四二硫键核心成员，在体外具有多种与生长和免疫相关的功能。尽管WFDC1在反应性基质中含量较低，但其体内功能尚不清楚。为了评估其核心功能，构建了Wfdc1基因敲除小鼠。Wfdc1基因敲除小鼠表现出正常的发育和成年表型。然而，稳态挑战影响了炎症和修复过程。感染甲型流感的Wfdc1基因敲除小鼠的病毒滴度相对于对照小鼠低2.75个对数级。Wfdc1基因敲除的感染肺中巨噬细胞增多，骨桥蛋白沉积增加，骨桥蛋白是一种有效的巨噬细胞趋化因子。在伤口研究中，Wfdc1基因敲除小鼠的皮肤闭合率升高，这也与骨桥蛋白沉积增加和巨噬细胞募集有关。Wfdc1基因敲除的成纤维细胞在体外表现出球体形成受损、对纤连蛋白的粘附增加以及伤口闭合率增加。用骨桥蛋白中和抗体可逆转这种情况。在用脂多糖或聚肌苷酸-聚胞苷酸处理的Wfdc1基因敲除细胞中，骨桥蛋白mRNA和裂解蛋白与组成型活性基质金属蛋白酶-9（MMP-9，一种裂解骨桥蛋白的蛋白酶）协同上调。这些数据表明，WFDC1/ps20部分通过调节骨桥蛋白和MMP-9的活性来调节宿主的核心反应机制。从WFDC1调节中释放可能是炎症和修复反应机制的关键组成部分，涉及活化的MMP-9对升高的骨桥蛋白的加工以及随后的巨噬细胞募集。
