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Bulk Transcriptome and Single-Cell Sequencing Datasets Reveal Key Programmed Cell Death Patterns in Radiation-Induced
Qiang Wang1,2,3, Chengcheng Xia1,2,3, Lihong Shao1,2,3
1Department of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.
Abstract:
Programmed cell death (PCD) has been implicated in the development and progression of radiation-induced lung injury (RILI). However, the specific PCD subtype most relevant to RILI remains unclear. We integrated bulk transcriptome datasets (GSE25295, GSE41789) and a single-cell RNA sequencing dataset (GSE211713) from lung tissue to analyze the cell type-specific PCD patterns in RILI. Differentially expressed genes (DEGs) were identified using limma for bulk data and Seurat for scRNA-seq data. PCD-related DEGs were extracted based on curated gene sets, followed by functional enrichment analyzes. Intercellular communication was assessed using CellChat, and transcription factor (TF) regulatory networks were constructed using RcisTarget and AUCell. Bulk transcriptome analyzes revealed 465 radiation-responsive genes enriched in inflammatory and immune pathways. Among multiple PCD subtypes, NETosis, a specialized form of neutrophil-driven PCD characterized by the release of neutrophil extracellular traps (NETs) composed of DNA and granule proteins, was the most significantly enriched in irradiated lung tissue (FDR < 0.05). Neutrophils showed the highest NETosis scores, accompanied by activation of MAPK, IL-17, TNF, and TLR signaling. CellChat analysis revealed enhanced bidirectional communication between neutrophils and AM1/IM1 through SPP1-CD44, ANXA1-FPR, and CCL/CXCL signaling. NETosis strongly correlated with M2 polarization, and key TFs (Mafg, Mxd4, Klf4, Max, Cux1, and Irf9) were identified as putative upstream regulators driving M2 macrophage polarization and neutrophil activation. Our findings highlight NETosis, mediated by enhanced neutrophil-macrophage crosstalk and TF-driven immune polarization.
Insights
NETosis, a form of programmed cell death involving neutrophils, is key in radiation-induced lung injury. This study reveals enhanced neutrophil-macrophage communication drives this process, offering new therapeutic targets.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Programmed cell death (PCD) is implicated in radiation-induced lung injury (RILI).
- The specific PCD subtype driving RILI pathogenesis remains largely undefined.
- Understanding cell-specific PCD is crucial for RILI treatment strategies.
Purpose of the Study:
- To identify the predominant programmed cell death (PCD) subtype in radiation-induced lung injury (RILI).
- To elucidate cell type-specific PCD patterns and intercellular communication networks in RILI.
- To uncover transcription factor (TF) regulatory networks governing RILI pathogenesis.
Main Methods:
- Integrated bulk and single-cell RNA sequencing data (GSE25295, GSE41789, GSE211713).
- Identified differentially expressed genes (DEGs) using limma and Seurat.
- Analyzed PCD subtypes, intercellular communication (CellChat), and TF networks (RcisTarget, AUCell).
Main Results:
- Bulk analysis identified 465 radiation-responsive genes linked to inflammation and immunity.
- NETosis, a neutrophil-driven PCD, was significantly enriched in irradiated lung tissue (FDR < 0.05).
- Neutrophils exhibited high NETosis scores, with enhanced communication with macrophages (AM1/IM1) via SPP1-CD44 and ANXA1-FPR signaling, correlating with M2 polarization.
Conclusions:
- NETosis is a critical PCD subtype in RILI pathogenesis.
- Enhanced neutrophil-macrophage crosstalk and TF-driven immune polarization are key mechanisms in RILI.
- Targeting NETosis and associated signaling pathways presents a potential therapeutic strategy for RILI.
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