Investigating the Intercellular Communication Network of Immune Cell in Acute Respiratory Distress Syndrome with Sepsis

Abstract

Acute respiratory distress syndrome (ARDS) is recognized as a serious public health issue that results in respiratory failure and high mortality rates. The syndrome is characterized by immune cell aggregation, communication, activation, and alveolar epithelial damage. To elucidate the complex dynamic process of the immune system's response in ARDS, we construct the intercellular communication network of immune cells in ARDS based on a single-cell RNA sequencing dataset (including three sepsis-induced ARDS patients and four sepsis-only patients). The results show that macrophages relayed most of the intercellular signals (ligand-receptor pairs) in both groups. Many genes related to immune response (IFI44L, ISG, and HLA-DQB1) and biological functions (response to virus, negative regulation of viral life cycle, and response to interferon-beta) were detected via differentially expressed gene analysis of macrophages between the two groups. Deep analysis of the intercellular signals related to the macrophage found that sepsis-induced ARDS harbored distinctive intercellular signals related to chemokine-chemokine receptors (CCL3/4/5-CCR1), which mainly are involved in the disturbance of the STAT family transcription factors (TFs), such as STAT2 and STAT3. These signals and downstream TFs might play key roles in macrophage M1/M2 polarization in the process of sepsis-induced ARDS. This study provides a comprehensive view of the intercellular communication landscape between sepsis and sepsis-induced ARDS and identifies key intercellular communications and TFs involved in sepsis-induced ARDS. We believe that our study provides valuable clues for understanding the immune response mechanisms of ARDS.

Figure 1

Characteristic of different immune cells. (a) t-SNE analysis for five clusters corresponding to five immune cells, respectively. (b) Correlation of immune cells. (c) Expression of markers related to classification of the five immune cells. (d) Intercellular signaling among different immune cell types. (e) Disease preference of macrophages and other immune cells for the same patient.

Figure 2

Differentially expressed gene (DEG) analysis and gene ontology functional enrichment analysis in macrophages. (a) Heatmap of DEGs in sepsis and sepsis-induced ARDS of macrophages. (b) Volcano plot displaying DEGs between the two groups in macrophages. (c) t-SNE analysis with top 20 major factors. (d) Gene ontology functional enrichment analysis with a total of 80 DEGs.

Figure 3

CellCall results and ridge plot of genes regulated by transcription factor (TF). (a) Intercellular signals from macrophage to other immune cells. (b) Ligand-receptor (LR) pairs between macrophage and other immune cells for two groups. (c) Downstream transcription factors (TFs) targeted by LR pairs in sepsis-induced ARDS and sepsis, and the width of each item means the frequencies of each pairs occurred among all the pairs, with the wider flow between two objects, the closer relation they have. (d) Ridgeline plot of genes regulated by TFs.