Aberrant endothelial CXCL signaling in COPD

Abstract

Rationale: Aberrant cell-cell signaling networks in Chronic Obstructive Pulmonary Disease (COPD) remain poorly understood. Therefore, we used single-cell RNA sequencing (scRNAseq) profiles to construct cell-cell signaling networks and infer alveolar signaling patterns that mediate COPD progression.

Methods: We analyzed scRNAseq data of explanted lung tissue from 17 patients with COPD and 15 control lungs, and validated findings using scRNAseq of mice exposed to 6 months of cigarette smoke. Connectomic networks were constructed by mapping the data against the FANTOM5 database of ligand-receptor pairs, and topological features of the networks were computed to explore dysregulated signaling. We then grouped cell-cell interactions into preassigned canonical signaling modes to identify pathway specific changes in cell-cell signaling. Finally, we explored specific ligand-receptor pairs that contributed the greatest changes in signaling.

Results: We generated networks of alveolar and immune cell signaling in both control and COPD lung tissue. We identified signaling changes in 14 out of 22 pathways, including CXCL, interleukin, and TNF. The largest increase was “outgoing” CXCL signaling from capillary endothelial cells, which was largely driven by increased CXCL12 signaling. Expression of CXCL12-interacting molecules, including CXCR3 and CXCR4, was also increased in "receiving" cell types. These findings were confirmed in our mouse model.

Conclusions: Our scRNAseq analysis reveals changes in alveolar signaling topology that occur in COPD, particularly increased capillary endothelial cell CXCL12 signaling, which may both underlie chronic inflammation in advanced COPD and represent a therapeutic target to treat this disease.