Multiomic analysis of monocyte-derived alveolar macrophages in idiopathic pulmonary fibrosis

Abstract Background Monocyte-derived alveolar macrophages (MoAMs) are increasingly recognised as potential pathogenic factors for idiopathic pulmonary fibrosis (IPF). While scRNAseq analysis has proven valuable in the transcriptome profiling of MoAMs, the integration analysis of multi-omics may provide additional dimensions of understanding of these cellular populations. Methods We performed multi-omics analysis on 116 scRNAseq, 119 bulkseq and five scATACseq lung tissue samples from IPF. We built a large-scale IPF scRNAseq atlas and conducted the Monocle 2/3 as well as the Cellchat to explore the developmental path and intercellular communication on MoAMs. We also reported the difference in metabolisms, tissue repair and phagocytosis between MoAMs and tissue-resident alveolar macrophages (TRMs). To determine whether MoAMs affected pulmonary function, we projected clinical phenotypes (FVC%pred) from the bulkseq dataset onto the scRNAseq atlas. Finally, we used scATATCseq to uncover the upstream regulatory mechanisms and determine key drivers in MoAMs. Results We identified three MoAMs clusters and the trajectory analysis further validated the origin of these clusters. Moreover, via the Cellchat analysis, the CXCL12/CXCR4 axis was found to be involved in the molecular basis of reciprocal interactions between MoAMs and fibroblasts through the activation of the ERK pathway in MoAMs. SPP1RecMacs (RecMacs, recruited macrophages) were higher in the low-FVC group than in the high-FVC group. Specifically, compared with TRMs, the functions of lipid and energetic metabolism as well as tissue repair were higher in MoAMs than TRMs. But, TRMs may have higher level of phagocytosis than TRMs. SPIB (PU. 1), JUNB, JUND, BACH2, FOSL2, and SMARCC1 showed stronger association with open chromatin of MoAMs than TRMs. Significant upregulated expression and deep chromatin accessibility of APOE were observed in both SPP1RecMacs and TRMs. Conclusion Through trajectory analysis, it was confirmed that SPP1RecMacs derived from Monocytes. Besides, MoAMs may influence FVC% pred and aggravate pulmonary fibrosis through the communication with fibroblasts. Furthermore, distinctive transcriptional regulators between MoAMs and TRMs implied that they may depend on different upstream regulatory mechanisms. Overall, this work provides a global overview of how MoAMs govern IPF and also helps determine better approaches and intervention therapies.