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Ontogenically distinct alveolar macrophages mediate cigarette smoke-induced inflammation and damage [RNA-Seq]

ABSTRACT: We employed bulk RNA sequencing to investigate how varying durations of cigarette smoke (CS) exposure affect alveolar macrophages (AM) of different ontogenies in mice. Chronic obstructive pulmonary disease (COPD) is often associated with CS and the third leading cause of death. While airway-recruited macrophages contribute to COPD pathogenesis, the role of embryonic AM (Em-AM) remains unclear. Using a CS-induced COPD mouse model, we found that CS-triggered lung inflammation and emphysema-like tissue damage correlated with substantial changes in the lung myeloid compartment. Using fate-mapping, we showed that, while most CS-induced AM were recruited bone marrow monocyte-derived AM (BM-AM), Em-AM persisted and underwent similar inflammation- and emphysema-associated adaptations as BM-AM upon CS. Therefore, our data support that the CS-exposed niche, rather than ontogeny, is the main determinant of AM fate in COPD, and that CS-induced AM changes may be potential therapeutic targets to mitigate AM dysfunction in COPD.

ORGANISM(S): Mus musculus

PROVIDER: GSE303772 | GEO | 2026/07/05

REPOSITORIES: GEO

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Ontogenically distinct alveolar macrophages mediate cigarette smoke-induced inflammation and damage

Project description:We employed single-cell RNA sequencing (scRNA seq) using the 10x Genomics platform to investigate how varying durations of cigarette smoke (CS) exposure affect myeloid cells of different ontogenies in mice. Chronic obstructive pulmonary disease (COPD) is often associated with CS and the third leading cause of death. While airway-recruited macrophages contribute to COPD pathogenesis, the role of embryonic alveolar macrophages (Em-AM) remains unclear. Using a CS-induced COPD mouse model, we found that CS-triggered lung inflammation and emphysema-like tissue damage correlated with substantial changes in the lung myeloid compartment. Using fate-mapping, we showed that, while most CS-induced AM were recruited bone marrow monocyte-derived AM (BM-AM), Em-AM persisted and underwent similar inflammation- and emphysema-associated adaptations as BM-AM upon CS. Therefore, our data support that the CS-exposed niche, rather than ontogeny, is the main determinant of AM fate in COPD, and that CS-induced AM changes may be potential therapeutic targets to mitigate AM dysfunction in COPD.

2026-07-05 | GSE303713 | GEO

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD

Project description:Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD pathogenesis is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures, as well as macrophages, accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to increased lung compliance, total lung capacity, and mean linear chord length in WT, but not B cell-deficient mice, associated with an increased size and number of iBALT structures. The increased accumulation of macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro co-culture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation. In summary, B cell function in iBALT formation in CS-induced emphysema provides a new innovative mechanism, which could be explored as a target for therapeutic intervention in COPD patients.

2014-12-04 | GSE52509 | GEO

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD

2014-12-04 | E-GEOD-52509 | biostudies-arrayexpress

Fibroblast growth factor (FGF) 10 is essential for lung morphogenesis

Project description:Fibroblast growth factor (FGF) 10 is essential for lung morphogenesis and polymorphisms in the Fgf10 region are linked with higher susceptibility towards COPD in human patients. We found that FGF10 signaling is impaired in lung septal wall compartment from COPD patients. Mice with impaired FGF10 signaling (Fgf10+/-) were more prone to develop cigarette smoke (CS)-induced emphysema and pulmonary hypertension (PH). Furthermore, FGF10 overexpression could successfully reverse cigarette smoke-induced emphysema and PH in mice.

2024-04-01 | GSE230854 | GEO

Adenine Nucleotide translocase 1 (ANT1) Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD

Project description:Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) has elevated ANT1 compared to normal control subjects. Ant1-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. Ant1-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional Ant1 knockout in Cx3cr1-positive monocytes and adoptive transfer of Ant1-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD

2025-03-31 | GSE287944 | GEO

Adenine Nucleotide translocase 1 (ANT1) Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD [6 months]

2025-03-31 | GSE289559 | GEO

Transcriptomic analysis of lung tissue from cigarette smoke induced emphysema murine models and human COPD show shared and distinct pathways

Project description:Although cigarette smoke (CS) is the primary risk factor for COPD, the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6J, NZW/LacJ) and two genetic models with mutations in COPD GWAS genes (HHIP, FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene response patterns that correlate with severity of emphysema in mouse and human lungs. Xenobiotic metabolism and Nrf2-mediated oxidative stress response were commonly regulated molecular response patterns across C57BL/6J, Hhip +/- and Fam13a -/- murine models upon chronic CS exposure and human COPD subjects. The CS resistant Fam13a -/- mouse and NZW/LacJ strain revealed an opposite pattern of gene expression response, suggesting distinct molecular pathways for resistance against emphysema. There were few genes commonly modulated between mouse and humans. Our study suggests gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS

2017-09-05 | GSE87292 | GEO

Molecular mechanisms of cigarette smoke-induced lung emphysema

Project description:Chronic obstructive pulmonary disease (COPD) is a complex pulmonary disorder primarily induced by cigarette smoking, and characterized by persistent airflow limitation. The mouse represents an important model for studying COPD pathologies such as lung emphysema. In this respect, a number of mechanistic studies have been performed, however the approaches were mostly focused on single gene analysis or characterization of cellular, inflammatory or histopathological changes without attempting a more comprehensive interpretation. In the present study we aimed at applying systems biology approach to identify genome-wide molecular mechanisms indicative of cigarette smoke (CS)-induced lung emphysema. The lung transcriptomes of five mouse models (C57BL/6, ApoE-/-, A/J, CD1, and Nrf2-/-), that are known to be susceptible to CS-induced emphysema development, were analyzed following prolonged (5-6 months) CS exposure. The investigation resulted in the confirmation of many existing mechanistic explanations underlying smoke-induced lung emphysema, including increased transcriptional activity of NF-?B, and increased levels of TNF-a, IFN-g, and IL-1b. More importantly, we predicted mechanisms without currently well-documented roles, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1 and N-cor, and increased IL-17 cytokine expression, and reduced protein expression of ITGB6 and CFTR. We also corroborated, by using targeted proteomic approaches, several predictions such as reduced expression of ITGB6 and increased expression of BRCA1, C/EBPs, PU.1, TNF-a, IL-1b or CSF2. We believe this study will provide more insights into better understanding of CS-induced molecular processes underlying emphysema development in mice that may eventually be relevant in humans.

2014-11-28 | E-MTAB-2756 | biostudies-arrayexpress

Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring

Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.

2015-01-21 | GSE65124 | GEO

Transcriptomic changes in bronchoalovelar derived macrophages after expsoure to whole body cigarette smoke exposure (8 weeks)

Project description:Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease characterized by emphysema and chronic bronchitis and a leading cause of mortality worldwide. COPD is commonly associated with several comorbid diseases which contribute to worse patient outcomes. Cigarette smoke (CS) is the most prominent risk factor for COPD development and progression and is known to be detrimental to numerous effector functions of lung resident immune cells, including phagocytosis and cytokine production. Methods: C57BL/6 mice were exposed to 8 weeks of CS as an experimental model of COPD. Airspace macrophages (AMs) were isolated from CS-exposed and RA mice and bulk RNA-Seq performed. The functional role of differentially expressed genes was assessed through gene ontology analyses. Ingenuity Pathway Analysis was used to determine the activation states of canonical pathways and upstream regulators enriched in differentially expressed genes in AMs. Results: CS induced decreased expression of genes involved in pathogen response, phagosome formation, and immune cell trafficking in AMs. Conclusions: CS exposure can induce transcriptomic remodelling in AMs. Our study highlights the ability of CS exposure to affect immune cell populations distal to the lung and warrants further investigation into the functional effects of these changes and the ensuing role in driving multimorbid disease.

2024-08-28 | GSE275328 | GEO

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