Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD.
J Cell Biol. 2019 Jan 7;218(1):333-349. doi: 10.1083/jcb.201802148. Epub 2018 Oct 26.
Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury and perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive tissue damage, are virtually unknown. In this study, we show that fibroblasts in injured tissues undertake the clearance of collectins by using the endocytic collagen receptor uPARAP. In cellular assays, several types of collectins were endocytosed in a highly specific uPARAP-dependent process, not shared by the closely related receptor MR/CD206. When introduced into dermis or bleomycin-injured lungs of mice, collectins MBL and SP-D were endocytosed and routed for lysosomal degradation by uPARAP-positive fibroblasts. Fibroblast-specific expression of uPARAP governed endogenous SP-D levels and overall survival after lung injury. In lung tissue from idiopathic pulmonary fibrosis patients, a strong up-regulation of uPARAP was observed in fibroblasts adjacent to regions with SP-D secretion. This study demonstrates a novel immune-regulatory function of fibroblasts and identifies uPARAP as an endocytic receptor in immunity.
收集素，如甘露聚糖结合凝集素（MBL）和表面活性剂蛋白 D（SP-D），在组织损伤后会暂时沉积在血管外间隙，并发挥免疫刺激或炎症限制功能。然而，为了防止过度的组织损伤，它们的转化机制实际上是未知的。在这项研究中，我们表明，受伤组织中的成纤维细胞通过使用内吞胶原受体 uPARAP 来清除收集素。在细胞试验中，几种类型的收集素以高度特异性的 uPARAP 依赖性方式被内吞，而这种方式与密切相关的受体 MR/CD206 不同。当将收集素 MBL 和 SP-D 导入小鼠真皮或博来霉素损伤的肺中时，uPARAP 阳性成纤维细胞会将其内吞并将其路由到溶酶体进行降解。成纤维细胞特异性表达 uPARAP 可控制内源性 SP-D 水平和肺损伤后的整体存活率。在特发性肺纤维化患者的肺组织中，在 SP-D 分泌区域附近的成纤维细胞中观察到 uPARAP 的强烈上调。这项研究证明了成纤维细胞的一种新的免疫调节功能，并确定 uPARAP 为免疫中的内吞受体。
