Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Nat Immunol. 2019 Feb;20(2):163-172. doi: 10.1038/s41590-018-0276-y. Epub 2019 Jan 14.
Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1SiglecF transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.
组织纤维化是一种主要的致死原因，它是由激活的间充质细胞沉积基质蛋白引起的。巨噬细胞在纤维化中积累，但在体内尚未研究特定亚群在支持纤维化形成中的作用。在这里，我们使用单细胞 RNA 测序 (scRNA-seq) 来描述小鼠博来霉素诱导的肺纤维化中巨噬细胞的异质性。一种新的通过参考批量转录组对 scRNA-seq 进行注释的计算框架（SingleR）使巨噬细胞能够进行亚聚类，并揭示了一个与疾病相关的亚群，其过渡基因表达谱介于单核细胞衍生的巨噬细胞和肺泡巨噬细胞之间。这些 CX3CR1SiglecF 过渡性巨噬细胞定位于纤维化部位，并在体内具有促纤维化作用。在特发性肺纤维化患者的样本中，表达过渡性巨噬细胞的基因的人类同源物上调。因此，我们已经确定了一种需要过渡性巨噬细胞来应对损伤的病理性亚群。
