Ding Wenjun, Deng Suihui, Wang Zhiping, Chen Xianjie, Xu Zhenyuan, Zhong Jun, Wu Xiaodan, Lin Ruiting, Ye Sen, Li Chun, Li Hui
State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China; Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University Haikou, China.
Int Immunopharmacol. 2025 Aug 28;161:114976. doi: 10.1016/j.intimp.2025.114976. Epub 2025 Jun 3.
Rapid pulmonary fibrosis (RPF) is a severe condition characterized by the rapid accumulation of excessive extracellular matrix (ECM), resulting in high mortality among patients with severe respiratory infections. CD163 macrophages were found to be enriched in RPF patients, their role in this disease requires elucidation.
We integrated single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) analyses of COVID-19-associated RPF patients, alongside an LPS three-hit-induced murine RPF model and in vitro co-culture systems. Genetic (CD163 mice) and functional (Osteopontin (OPN) silencing) approaches were employed to dissect the profibrotic role of CD163 macrophages.
scRNA-seq and snRNA-seq analyses identified an enrichment of CD163 macrophages in the lungs of COVID-19 patients with RPF, along with upregulated expression of fibrosis-associated genes, such as SPP1 (encoding OPN). In the murine model, CD163 macrophages promoted RPF progression, with OPN expression positively correlating with collagen deposition. Moreover, silencing OPN impaired the profibrotic activity of CD163 macrophages in vitro.
CD163 macrophages are enriched in rapid pulmonary fibrosis patients and the mouse model, facilitating disease progression through the secretion of OPN. The CD163 macrophage-OPN axis could be a potential therapeutic target for rapid pulmonary fibrosis.
快速进展性肺纤维化（RPF）是一种严重疾病，其特征是细胞外基质（ECM）快速过度积累，导致重症呼吸道感染患者死亡率很高。研究发现CD163巨噬细胞在RPF患者中富集，其在该疾病中的作用有待阐明。
我们整合了新冠病毒相关RPF患者的单细胞RNA测序（scRNA-seq）和单核RNA测序（snRNA-seq）分析，以及脂多糖三打击诱导的小鼠RPF模型和体外共培养系统。采用遗传学方法（CD163小鼠）和功能学方法（沉默骨桥蛋白（OPN））来剖析CD163巨噬细胞的促纤维化作用。
scRNA-seq和snRNA-seq分析确定了RPF的新冠病毒患者肺中CD163巨噬细胞富集，同时纤维化相关基因如SPP1（编码OPN）的表达上调。在小鼠模型中，CD163巨噬细胞促进RPF进展，OPN表达与胶原沉积呈正相关。此外，沉默OPN会损害CD163巨噬细胞在体外的促纤维化活性。
CD163巨噬细胞在快速进展性肺纤维化患者和小鼠模型中富集，通过分泌OPN促进疾病进展。CD163巨噬细胞-OPN轴可能是快速进展性肺纤维化的潜在治疗靶点。
