Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis.
Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis.
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DOI：
10.1183/13993003.02441-2018
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发表时间：
2019-08
期刊：
影响因子：
--
通讯作者：
Lafyatis R
中科院分区：
文献类型：
--
作者：
Morse C;Tabib T;Sembrat J;Buschur KL;Bittar HT;Valenzi E;Jiang Y;Kass DJ;Gibson K;Chen W;Mora A;Benos PV;Rojas M;Lafyatis R
全面了解特发性肺纤维化(IPF)相关细胞类型基因表达的变化将有助于阐明肺泡上皮细胞丢失、蜂窝囊肿和成纤维细胞灶形成的机制。我们试图了解IPF肺细胞转录本的变化，并深入了解发病机制的先天免疫方面。我们用新鲜肺外植体的单细胞RNA测序方法研究了IPF的发病机制，比较了反映晚期疾病的人IPF纤维化下叶、反映早期疾病的上叶和正常肺。IPF下叶成纤维细胞增多，基底细胞、纤毛细胞、杯状细胞和棒状细胞增多，肺泡上皮细胞减少，炎症细胞明显改变。我们在正常肺和纤维化肺中发现了三个离散的巨噬细胞亚群，一个表达单核细胞标志物，一个高表达FABP4和INHBA(FABP4hi)，一个高表达SPP1和MERTK(SPP1hi)。纤维化下叶的巨噬细胞SPP1和MERTK表达高度上调。正常肺SPP1hi巨噬细胞局部低水平增殖在IPF肺明显增强。共定位和因果模型支持这些高增殖的SPP1hi巨噬细胞在肺纤维化中IPF肌成纤维细胞激活中的作用。这些数据表明，SPP1hi巨噬细胞在IPF的肺纤维化中起重要作用，针对MERTK和巨噬细胞增殖的治疗策略可能显示出治疗这种疾病的前景。
A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells, and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis. We investigated IPF pathogenesis using single cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs. IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs. Co-localization and causal modeling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
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影响因子：
10
作者：
Dong J;Ma Q
通讯作者：
Ma Q
影响因子：
20.1
作者：
DeBerge M;Yeap XY;Dehn S;Zhang S;Grigoryeva L;Misener S;Procissi D;Zhou X;Lee DC;Muller WA;Luo X;Rothlin C;Tabas I;Thorp EB
通讯作者：
Thorp EB
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
34.7
作者：
Brown, Guy C.;Neher, Jonas J.
通讯作者：
Neher, Jonas J.
DOI：
10.1084/jem.194.6.809
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee CG;Homer RJ;Zhu Z;Lanone S;Wang X;Koteliansky V;Shipley JM;Gotwals P;Noble P;Chen Q;Senior RM;Elias JA
通讯作者：
Elias JA