Alveolar macrophage transcriptomic profiling in COPD shows major lipid metabolism changes

Fujii, Wataru; Kapellos, Theodore S.; Baßler, Kevin; Händler, Kristian; Holsten, Lisa; Knoll, Rainer; Warnat-Herresthal, Stefanie; Oestreich, Marie; Hinkley, Emily; Hasenauer, Jan; Pizarro, Carmen; Thiele, Christoph; Aschenbrenner, Anna C.; Ulas, Thomas; Skowasch, Dirk; Schultze, Joachim L.

doi:10.1183/23120541.00915-2020

Cited by 33 publications

(30 citation statements)

References 66 publications

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“…19,51,57,58 . In contrast to a recent study of the COPD alveolar macrophage transcriptome 48 , we did not see signs of altered lipid metabolism in alveolar macrophage expression signatures. However, this previous study included more severe and predominantly smoking COPD patients, which may explain differences with our observations.…”

Section: Discussioncontrasting

confidence: 99%

“…A recent study in Cd44-/-knockout mice, demonstrated that deficiency of CD44 on alveolar macrophages, disrupted surfactant lipid homeostasis 44 . We analysed the transcriptome of purified BAL macrophages (demographics for included participants given in Table S3) and found no significant activation of transcriptomic pathways involved in macrophage lipid turnover or potentially involved in surfactant metabolism using either differentially expressed gene (DEG) analysis or WGNCA (Figure S3) 48 .…”

Section: Alveolar Macrophage Gene Expressionmentioning

confidence: 99%

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Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

et al. 2022

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RationalePulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and anti-pathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD.ObjectivesWe investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights about potential disease mechanisms.MethodsBronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed.ResultsTotal phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and surfactant protein (SP)-B, SP-A and SP-D concentrations were lower, COPDversuscontrols, log2 fold change (log2FC)=−2.0, −2.2, −1.5, −0.5, −0.7, −0.5 (adj. p-value<0.02), respectively, and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and SP-A, SP-B, SP-D, NAPSA and CD44 inversely correlated with CT small airways disease measures (E/I MLD), r=−0.56, r=−0.58, r=−0.45, r=−0.36, r=−0.44, r=−0.37, r=−0.40, r=−0.39 (adj. p-value<0.05). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (%LAA): r=−0.55, r=−0.61, r=−0.48, r=−0.51, r=−0.41, r=−0.31, r=−0.34, respectively (adj. p-value<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated, COPDversuscontrols, log2FC of 0.40 (adj. p-value=0.0390) and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPDversusHV-ES, and predicted COPD status, AUC=0.85.ConclusionsUsing a multiomics approach we, for the first time, demonstrate global surfactant dysregulation in COPD which was associated with emphysema giving new insights about potential mechanisms underlying the cause or consequence of disease.

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Section: Discussioncontrasting

confidence: 99%

Section: Alveolar Macrophage Gene Expressionmentioning

confidence: 99%

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

et al. 2022

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“…Disorders of pulmonary lipid metabolism are a well-known pathophysiological characteristic of the processes that are associated with the progression of COPD [ 180 , 207 ]. These changes affect predominantly macrophages, thus providing a close link between impaired pulmonary lipid metabolism and the innate immune response [ 178 ].…”

Section: Lipid Metabolism Disorders In the Development And Progression Of Copdmentioning

confidence: 99%

Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease

Kotlyarov

Bulgakov

2021

Cells

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Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.

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“…In response to inflammatory stimuli, AMs secrete cytokines and chemokines to initiate the immune response. Subsequently, AMs and recruited monocytes contribute to the resolution of the inflammatory response to prevent excess damage ( Janssen et al, 2011 ; Mould et al, 2017 ; Fujii et al, 2021 ; Hetzel et al, 2021 ). In addition, they play a major role in maintaining lipid homeostasis in the lung, which is essential for adequate gas exchange and alveolar epithelial integrity.…”

Section: Introductionmentioning

confidence: 99%

ScRNA-seq expression ofIFI27andAPOC2identifies four alveolar macrophage superclusters in healthy BALF

Kolling

Aridgides

et al. 2022

Life Sci. Alliance

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Alveolar macrophages (AMs) reside on the luminal surface of the airways and alveoli, ensuring proper gas exchange by ingesting cellular debris and pathogens, and regulating inflammatory responses. Therefore, understanding the heterogeneity and diverse roles played by AMs, interstitial macrophages, and recruited monocytes is critical for treating airway diseases. We performed single-cell RNA sequencing on 113,213 bronchoalveolar lavage cells from four healthy and three uninflamed cystic fibrosis subjects and identified two MARCKS+LGMN+IMs, FOLR2+SELENOP+ and SPP1+PLA2G7+ IMs, monocyte subtypes, DC1, DC2, migDCs, plasmacytoid DCs, lymphocytes, epithelial cells, and four AM superclusters (families) based on the gene expression of IFI27 and APOC2. These four AM families have at least eight distinct functional members (subclusters) named after their differentially expressed gene(s): IGF1, CCL18, CXCL5, cholesterol, chemokine, metallothionein, interferon, and small-cluster AMs. Interestingly, the chemokine cluster further divides with each subcluster selectively expressing a unique combination of chemokines. One of the most striking observations, besides the heterogeneity, is the conservation of AM family members in relatively equal ratio across all AM superclusters and individuals. Transcriptional data and TotalSeq technology were used to investigate cell surface markers that distinguish resident AMs from recruited monocytes. Last, other AM datasets were projected onto our dataset. Similar AM superclusters and functional subclusters were observed, along with a significant increase in chemokine and IFN AM subclusters in individuals infected with COVID-19. Overall, functional specializations of the AM subclusters suggest that there are highly regulated AM niches with defined programming states, highlighting a clear division of labor.

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Alveolar macrophage transcriptomic profiling in COPD shows major lipid metabolism changes

Cited by 33 publications

References 66 publications

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD

Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease

ScRNA-seq expression ofIFI27andAPOC2identifies four alveolar macrophage superclusters in healthy BALF

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