Single-cell sequencing unveils a profibrotic macrophage and infiltrating monocyte niche in the bronchoalveolar lavage of patients with chronic obstructive pulmonary disease

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by global immune dysregulation. The most abundant immune cells in the distal airways and alveolar compartments are macrophages and lymphocytes. These cells have been poorly characterized in human airways due to their plasticity and numerous subtypes. There is a marked scarcity of information in the COPD airway, limiting our understanding of the inflammatory process that drives COPD progression.

Objectives: The primary aim of this study was to characterize the differences in composition of the immune cells in the alveolar space of patients with COPD versus healthy controls and the relation with severity of airflow limitation at a single-cell resolution.

Methods: Individuals with and without COPD were recruited. All participants underwent bronchoscopy, where a single-cell suspension was created from the retrieved bronchoalveolar lavage and then sequenced using single-cell RNA sequencing technology. Full pulmonary function tests, thoracic computed tomography (CT), and xenon-129 hyperpolarized gas magnetic resonance imaging (MRI) were performed on participants for phenotyping.

Measurements and main results: From 17 participants, a total of 97 254 cells were recovered, with 52 840 cells belonging to the COPD group (N = 10). The COPD immune landscape was perturbed and characterized by an expansion of non-typable macrophages, increased neutrophils and classical monocytes, and significant changes in regulatory and double-negative T lymphocytes compared to controls (FDR < 0.05). The percentage of these cells was further altered with increasing GOLD (Global Initiative for Chronic Obstructive Lung Disease) severity stages. The percentage of double-negative T cells in BAL was significantly related to airway luminal area on CT, whereas that of regulatory T cells was inversely related to MRI gas transfer and DLCO of COPD patients.

Conclusions: The immune cell transcriptomic profile of COPD BAL reveals global immune dysregulation, with increased abundance of proinflammatory and profibrotic macrophages, monocytes, and neutrophils, potentially driving airway remodeling. Regulatory T cells may play a significant role in gas exchange perturbations of COPD.

Keywords: chronic obstructive pulmonary disease; fibrosis; immune cells inflammation; single-cell RNA sequencing.