Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling

Abstract

Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling.

Dissecting causal relationships between immune cells, plasma metabolites, and COPD: a mediating Mendelian randomization study

“…Our analysis identified six immune cell phenotypes with a causal relationship to COPD in both directions, namely CD14+ CD16+ monocyte AC, CD4+ CD8dim %lymphocyte, CD4+ CD8dim %leukocyte, CD3- lymphocyte AC, CD3 on EM CD8br, and CD45 on Im MDS, all associated with a reduced risk of COPD. The CD14+ CD16+ monocyte AC, a monocyte subgroup expressing CD14 and CD16, plays a role in modulating inflammatory responses and promoting tissue repair, with monocytes being etiologically related to COPD ( 53 ) and influencing its pathogenesis and diagnosis ( 54 , 55 ), serving as key drivers of lung inflammation and tissue remodeling ( 56 ). The CD4+ CD8dim %lymphocyte, a unique lymphocyte, plays a role in regulating immune responses and maintaining immune balance, with CD4-regulated T cells controlling autoimmunity and thus managing lung inflammation in COPD ( 57 , 58 ), while CD4 and CD8 are related to bronchiolar wall remodeling in COPD ( 59 ) and the reduction of terminal bronchioles ( 60 ).…”