Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation

Abstract

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Tobacco smoke exposure results in recruitment of inflammatory airspace monocytes and accelerated growth ofMycobacterium tuberculosis

“…One study found a decrease of CD16 expression and slight increase of CD14 expression on the surface of BAL cells from smokers and COPD patients, consistent with the CD14+ monocyte phenotype in our cohort (35). Intriguingly, using scRNA-seq, characterization of airspace monocytes which differentiate further into a number of macrophage phenotypes has also been described in patients with COVID-19 and COPD, confirming the connection between inflammation, disease, and recruited monocytes across multiple disease contexts (18,(37)(38)(39). We specifically identify CD93 as a novel marker for defining a disease-relevant population of airspace monocytes, enriched in smokers' airspaces.…”

“…Both airspace monocytes and macrophages exhibited elevated expression of genes involved in phagocytosis and antigen processing/presentation as compared to blood monocytes from the same subjects (Figure 1G and Figure S3B), supporting the interpretation that airspace monocytes are a differentiating cell population. As external support from a separate human disease cohort, we compared our airspace monocyte population against work from Baβler et al ( 18 ), who identified a population of monocytes differentiating into macrophages that was enriched in BAL samples from smokers with chronic obstructive pulmonary disease (COPD). Our smoking-associated airspace monocytes strongly and specifically expressed markers from a population of differentiating monocytes (i.e., elevated compared to blood-derived monocytes and AM alike) identified in Baβler et al, further supporting that airspace monocytes accumulate in smokers and may serve as precursors to other tissue macrophage states (Figure S3C-E).…”

Identification and Analysis of Necroptosis-Related Genes in COPD by Bioinformatics and Experimental Verification

“…It has been demonstrated that the heterogeneity of macrophages and the activation of T cells are dependent on external stimuli and the microenvironment [ 68 ]. Several factors, including smoking status, severity of COPD, acute exacerbations, and corticosteroid use, may contribute to different conclusions [ 69 , 70 , 71 ]. Additionally, in the validation dataset, the degree of neutrophil infiltration was enhanced in lung tissue samples from COPD patients, which has been extensively demonstrated in previous studies [ 72 , 73 ].…”

“KEAP”ing Alveolar Macrophage Mitochondria Content in Chronic Obstructive Pulmonary Disease

“…Chronic obstructive pulmonary disease (COPD) is associated with persistent macrophage infiltration in the lung parenchyma and alveolar space even after smoking cessation ( 1 ), which correlates with disease severity and areas of lung destruction ( 2 ). Macrophages isolated from BAL in COPD are derived from both tissue-resident macrophages with the capacity for self-renewal and circulating peripheral blood monocytes that migrate to the lung under a variety of stimuli ( 3 , 4 ). Despite the increased abundance of airway and alveolar macrophages (hereafter termed alveolar macrophages [AMs]) in COPD, recurrent respiratory infections are abundant, accelerating disease progression and mortality ( 5 ).…”

“…For example, stimulated bone marrow–derived macrophages predominantly use glycolysis ( 11 ) to rapidly generate ATP for proinflammatory effector functions, whereas AMs that inhabit a low-glucose, high-lipid environment in the healthy lung rely on OXPHOS to meet energy demands ( 12 , 13 ). AMs from individuals with COPD display a defect in mitochondrial respiration ( 10 , 13 ), with lower compensatory glycolysis and alterations in metabolite abundance ( 4 , 12 ). Yet how this metabolic rewiring relates to the functional capacity of AMs and whether this phenomenon can be therapeutically reversed with beneficial effects had yet to be defined.…”