Multiomic analysis of monocyte-derived alveolar macrophages in idiopathic pulmonary fibrosis
Miaomiao Zhang1,2, Jinghao Zhang3, Haisheng Hu1
1Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Background:
Monocyte-derived alveolar macrophages (Mo_AMs) are increasingly recognised as potential pathogenic factors for idiopathic pulmonary fibrosis (IPF). While scRNAseq analysis has proven valuable in the transcriptome profiling of Mo_AMs, 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 Mo_AMs. We also reported the difference in metabolisms, tissue repair and phagocytosis between Mo_AMs and tissue-resident alveolar macrophages (TRMs). To determine whether Mo_AMs 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 Mo_AMs.
Results:
We identified three Mo_AMs 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 Mo_AMs and fibroblasts through the activation of the ERK pathway in Mo_AMs. SPP1_RecMacs (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 Mo_AMs 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 Mo_AMs than TRMs. Significant upregulated expression and deep chromatin accessibility of APOE were observed in both SPP1_RecMacs and TRMs.
Conclusion:
Through trajectory analysis, it was confirmed that SPP1_RecMacs derived from Monocytes. Besides, Mo_AMs may influence FVC% pred and aggravate pulmonary fibrosis through the communication with fibroblasts. Furthermore, distinctive transcriptional regulators between Mo_AMs and TRMs implied that they may depend on different upstream regulatory mechanisms. Overall, this work provides a global overview of how Mo_AMs govern IPF and also helps determine better approaches and intervention therapies.
Insights
Monocyte-derived alveolar macrophages (Mo_AMs) contribute to idiopathic pulmonary fibrosis (IPF) by interacting with fibroblasts. These Mo_AMs, distinct from tissue-resident alveolar macrophages (TRMs), influence lung function and disease progression.
Area of Science:
- Pulmonary Medicine
- Immunology
- Genomics
Background:
- Monocyte-derived alveolar macrophages (Mo_AMs) are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF).
- Multi-omics analysis offers deeper insights into Mo_AMs beyond scRNAseq.
Purpose of the Study:
- To comprehensively analyze Mo_AMs in IPF using multi-omics data.
- To explore the developmental trajectory and intercellular communication of Mo_AMs.
- To elucidate the regulatory mechanisms and functional differences of Mo_AMs in IPF.
Main Methods:
- Performed multi-omics analysis (scRNAseq, bulkseq, scATACseq) on IPF lung tissues.
- Utilized Monocle and CellChat for trajectory and communication analysis of Mo_AMs.
- Compared Mo_AMs with tissue-resident alveolar macrophages (TRMs) regarding metabolism, repair, and phagocytosis.
Main Results:
- Identified three Mo_AMs clusters and confirmed their monocytic origin.
- The CXCL12/CXCR4 axis mediates Mo_AM-fibroblast communication, activating the ERK pathway.
- Mo_AMs exhibit distinct metabolic and tissue repair functions compared to TRMs, potentially impacting lung function (FVC%pred).
Conclusions:
- Mo_AMs, specifically SPP1_RecMacs, are derived from monocytes and contribute to IPF progression.
- Mo_AMs influence pulmonary function and fibrosis severity through fibroblast interactions.
- Distinct transcriptional regulators suggest different upstream mechanisms for Mo_AMs and TRMs, guiding therapeutic strategies.
