Characterizing the B-cell senescence signature in driving the disease phenotype in COPD/emphysema

Abstract

Increased cellular senescence is a key mechanism underlying chronic inflammation and airway remodeling in chronic obstructive pulmonary disease (COPD). Yet, the cellular composition and molecular features of the senescent microenvironment in COPD remain poorly understood. To address this gap, we employed a multi-omics approach to identify senescence-associated differentially regulated cell populations and associated genes in smoke-induced emphysema. Single-cell RNA sequencing analyses of 121,885 lung cells from COPD patients and healthy controls (n = 6 per group), including individuals with (Sm) and without (NS) a smoking history, were analyzed using standard approaches. Our analyses reveal a significant enrichment (p < 0.05) of senescence-associated gene signatures within B-cell clusters from COPD lungs. The transcriptional profile of senescent B cells include: (a) impairment of B cell differentiation and maturation (KITLG, PRDM1), (b) increase in inflammatory signaling (CXCL3, IL6, GDF15), and (c) dysregulation of lipid metabolism (PTGS2), thereby releasing factors affecting ECM composition (MMP14) and cell-cell interactions in COPD. Spatial transcriptomics and proteomics validate the scRNA seq findings. We identify distinct ‘senescent’ niches within COPD lungs that shows persistent inflammatory signaling, activation of p16-mediated senescence, and dysregulation of intercellular communication. Notably, we report a shift toward ADGRE5-CD55 ligand–receptor interactions between B lymphocytes and alveolar type II (AT2) cells in senescent regions in COPD donor tissues. Together, these findings identify and characterize B-cell senescence as a feature of the COPD lung microenvironment providing novel insight into the mechanistic underpinning of pathophysiology in COPD. Premature lung aging remains a well-known feature in smokers with Chronic Obstructive Pulmonary Disease (COPD). While previous attempts have been made to design therapies to reverse the smoking-induced lung aging, progress in this regard remains challenging. Here, we use modern state-of-the-art techniques to identify the cell population playing a central role in affecting premature lung aging during disease development amongst chronic smokers. Successful validation of our study findings was performed using fresh lung tissues and blood plasma from healthy and COPD patients to identify possible cell types and biomolecules that could be targeted as therapies in future for this debilitating disease. Kaur et al., profile senescence-associated cell populations in COPD using single-cell RNA sequencing of 121,885 lung cells, supported by spatial transcriptomics and proteomics, to define the senescent lung microenvironment. Senescent B cells are enriched in COPD lungs and exhibit inflammatory, differentiation, and lipid metabolism abnormalities that define distinct senescent niches with altered cell-cell communication, including enhanced ADGRE5-CD55 signaling between B cells and alveolar type II cells.