Single cell omics identify an anti-inflammatory niche in macrophages of mild to moderate chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major contributor to global mortality rates, yet the cell-specific mechanisms underlying its pathobiology remain poorly understood, particularly in mild disease stages. Single-cell profiles of lung tissues from individuals with mild to moderate COPD or control lungs were analyzed using Microwell-seq. Transcriptomic findings were validated using microfluidic single-cell RNA sequencing of murine lungs, high-throughput single-nucleus total RNA sequencing (snHH-seq) of human lung tissues from severe COPD, spatial transcriptomics, functional in vitro models, and immunostaining of human lung samples. An increased subpopulation, termed interstitial COPD-associated macrophages (ICM), was identified, with transcriptional evidence of anti-inflammatory activity and reduced the transcription of proteins associated with elastase secretion in mild to moderate COPD. Comprehensive analysis of single-cell datasets revealed enhanced expression of Secretoglobin 3A2 (SCGB3A2) and macrophage receptor with collagenous structure (MARCO) across epithelial secretory cells and interstitial macrophages. Transcriptomic data demonstrated that MARCO activation was pivotal for phenotypic changes in interstitial macrophages (IM) transitioning to alveolar macrophages (AM). Spi-1 proto-oncogene (SPI1) transcription factor levels aligned with the MARCO transcriptome in ICM derived from COPD. In mild to moderate COPD, secretory cells play protective roles by regulating ICM through the SCGB3A2-MARCO pathway. Targeting ICM for COPD treatment may preserve the anti-inflammatory interstitial environment in patients.