Lung-resident non-classical monocytes are involved in systemic inflammation in chronic obstructive pulmonary disease

<bold>Rationale:</bold> Systemic inflammation is one of the systemic manifestations of chronic obstructive pulmonary disease (COPD). However, little is known about the role of lung-resident monocytes in this process. This study aims to elucidate an association of lung monocytes with systemic inflammation and their single-cell transcriptomics in COPD. <bold>Methods:</bold> We collected cells from non-cancerous tissues of patients who underwent lung resections for primary lung cancer. A flow-cytometric analysis identified lung classical monocytes (CMs), intermediate monocytes (IMs) and non-classical monocytes (NCMs) as CD14⁺CD16^low, CD14⁺CD16^mid and CD14⁺CD16^high cells, respectively. We evaluated correlations between each monocyte subset and clinical parameters such as C-reactive protein (CRP). We analysed a single-cell RNA sequencing dataset (GSE136831) of lung cells from non-COPD (n=20) and COPD (n=18) patients. <bold>Results:</bold> The percentage of NCMs to total CD45⁺ cells was significantly increased in COPD patients (n=10, 0.45% [IQR 0.16-1.08%]) compared to control never smokers (n=10, 0.027% [0.016-0.032%], p=0.0002) and control ex-smokers (n=10, 0.08% [0.02-0.13%], p=0.0332). A multiple linear regression analysis indicated an independent correlation between NCMs and CRP (p=0.0012), but not CMs or IMs. The expression of genes associated with apoptotic cell clearance (<italic>CX3CR1</italic>, <italic>MERTK</italic>, <italic>CD14</italic>) was downregulated in COPD lung NCMs. <bold>Discussion:</bold> NCMs are widely known to have a role in intravascular phagocytes. Taken together, our results suggest that intravascular apoptotic cell clearance of lung-resident NCMs is impaired in patients with COPD, leading to an increase in systemic inflammation.