1. Institute of Clinical Pathology, Key Laboratory of Transplantation Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
2. Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
3. West China Second Hospital, Sichuan University, Chengdu, 610041 P. R. China & Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education.
*These authors contributed equally to this work.
There is growing support for the notion that chronic inflammation contributes to lung tumorigenesis, but the molecular and cellular basis underlying the protumorigenic effects of inflammation remains to be explored. 3-Methylcholanthrene and diethylnitrosamine were intratracheally instilled into rats to induce multistep lung carcinogenesis, and the presence of pulmonary inflammation was observed in addition to precancerous lesions. By leveraging single-cell RNA sequencing, we sought to unravel the mechanism underlying the inflammatory process at a higher resolution. A total of 14 cell types were identified in chemically treated and control rats. Chemical intervention introduced heterogeneity in cell type composition and gene expression patterns. Nonimmune cells were found to be the most affected, and two subpopulations of endothelial cells with diverse roles were defined. Car4-high endothelial cells were mainly responsible for angiogenesis, whereas Car4-low endothelial cells were involved in neutrophil recruitment, and adhesion between Car4-low endothelial cells and neutrophils was verified in inflamed tissues. Our work unveiled the intricate process of pulmonary inflammation at the single-cell level and characterized a proinflammatory subpopulation of endothelial cells involved in neutrophil recruitment. The conditions provided by chronic inflammatory environment are prerequisites for neoplastic progression. Targeting the specific subsets or processes defined herein holds promise for the early prevention and therapeutic intervention of lung cancer through the manipulation of angiogenesis or the inflammatory response.
Keywords: pulmonary inflammation, single-cell RNA sequencing, endothelial cell, neutrophil recruitment