Integrative single-cell RNA-seq and ATAC-seq analysis reveals the key role of inflammatory cell activation in pulmonary arterial hypertension

Background The cellular heterogeneity and molecular complexity of pulmonary arterial hypertension (PAH) have not been fully elucidated. Methods Here, we constructed an integrative transcriptome and chromatin accessibility atlas of PAH mice by using single-cell RNA sequencing and single-cell ATAC sequencing. Results In PAH mice, the numbers of granulocytes and monocytes/macrophages in the lung tissues were increased, and the hypoxia-inducing factor pathway was specifically activated in these inflammatory cells. Furthermore, monocyte/macrophage subcluster analysis revealed an increase of chemokine C-C-motif receptor 2 (CCR2) + proinflammatory macrophages but a decrease of M2-like macrophages. Notably, S100a9 expression was significantly upregulated in both granulocytes and CCR2 + proinflammatory macrophages, accompanied by increased chromatin accessibility at the promoter region specifically in CCR2 + macrophages. Given its restricted upregulation in these two key proinflammatory cell populations, we generated S100a9 global knockout mice to investigate its role in PAH. S100a9 deletion alleviated the pulmonary arterial remodeling and right ventricular dysfunction in PAH mice. Conclusion In conclusion, this study established a comprehensive transcriptome and chromatin accessibility atlas for PAH mice and further indicated that activation of S100a9-expressing inflammatory cell might be associated with the development of PAH. Further researches are warranted to investigate the underlying mechanisms.