Fatma Saaoud1
Keman Xu1
Yifan Lu1
Ying Shao1
Baosheng Han1
Xianwei Wang2Xiaohua Jiang1,2
Xiaolei Liu1
Jianhai Du3
Hong Wang2
Beata Kosmider4*
Xiaofeng Yang1,2*- 1Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- 2Metabolic Disease Research and Thrombosis Research Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- 3Department of Ophthalmology and Visual Sciences, West Virginia University School of Medicine, Morgantown, WV, United States
- 4Center for Inflammation and Lung Research, Department of Microbiology, Immunology and Inflammation, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory disorder characterized by persistent immune dysregulation and progressive structural deterioration of the lung. However, how COPD reshapes lung architecture, immune signaling, and cellular identity at a systems level remains incompletely understood.
Methods: We performed integrative, multi-dimensional transcriptomic analysis of human COPD lung datasets to evaluate alterations in immune signaling, regulated cell death pathways, fibrosis-associated programs, cell type–specific transcriptional identity, and immune checkpoint regulation. Genetic and cytokine-based perturbations targeting trained immunity pathways were analyzed to assess functional relevance.
Results: COPD induced broad transcriptional activation of cytokines, secretory and plasma membrane proteins, CD markers, innate immune genes, and trained immunity genes. Deficiency of SET7, a promoter of trained immunity, or overexpression of IL-37, an inhibitor of trained immunity, attenuated expression of COPD-upregulated immune genes. COPD also promoted tissue injury through coordinated upregulation of genes regulating multiple forms of regulated cell death, including autosis, autophagy, parthanatos, immunogenic cell death, mitochondrial permeability transition-associated death, lysosomal cell death, apoptosis, necroptosis, ferroptosis, mitotic cell death, and proliferation-associated cell death. In parallel, COPD enhanced epithelial-to-mesenchymal transition and fibrosis-related transcriptional programs. Transcriptomic identity was disrupted in 10 of 14 major human lung cell types, with evidence of pathological trans-differentiation marked by aberrant expression of over 50 cell type-specific marker genes. Alveolar macrophages exhibited extensive dysregulation of immune checkpoint ligand; notably, PVR (CD155) expression was reduced in severe emphysema, while experimental PVR overexpression suppressed pro-inflammatory gene expression in both alveolar and interstitial macrophages. Additionally, COPD impaired the suppressive capacity of CD4+Foxp3+ regulatory T cells through downregulation of key immunosuppressive genes, including those associated with FoxP3+, TIGIT+, and LPS-responsive Tregs. Shared immunosuppressive gene signatures were identified between PVR-overexpression-inducing CD4+ T cells and IL-10-mediated regulatory pathways in T cells and monocytes.
Discussion: Collectively, these findings demonstrate that COPD reprograms the lung toward an immune-like organ by promoting immune cell-like trans-differentiation of structural cells, activating diverse regulated cell death pathways, and altering immune checkpoint signaling. These mechanisms highlight potential therapeutic targets for immunomodulatory intervention in COPD.
1 Introduction
Chronic obstructive pulmonary disease (COPD) is a major public health burden and a leading cause of morbidity and mortality in the United States, accounting for approximately 15.4 million physician visits, 1.5 million emergency department visits, and 726,000 hospitalizations annually (1). Globally, COPD affects ∼ 10% of adults over 40 years and remains the third leading cause of death worldwide (2, 3). COPD is a progressive and heterogeneous disease characterized by chronic airway inflammation, airflow obstruction, and alveolar destruction (emphysema), ultimately resulting in irreversible loss of lung function (4). Impaired host defense mechanisms increase susceptibility to pathogens, pollutants, toxic chemicals, and allergens, establishing a dynamic interplay between environmental exposures and immune responses. These exposures perturb the lung microbiome and disrupt immunoregulatory pathways, contributing to chronic inflammation and disease progression. COPD encompasses multiple clinical phenotypes that are thought to rises from distinct molecular endotypes (5).
Beyond the lung, chronic pulmonary inflammation leads to systemic spillover of cytokines, chemokines, and other inflammatory mediators (6), promoting low-grade systemic inflammation and a broad spectrum of comorbidities, including cardiovascular disease (7), pulmonary vascular disease, venous thromboembolism, metabolic dysfunction, diabetes, lung cancer, neuropsychiatric disorders, osteoporosis, anemia, and cognitive impairment (8). We recently reported that up to 53% of human proteins can be secreted during inflammation through six distinct pathways, including canonical, caspase-1-dependent, caspase-4/11-dependent, exosome-mediated (9), Weibel-Palade body-mediated, and autophagy-mediated release (10).
Epithelial–mesenchymal transition (EMT) is a key pathological process in COPD, where airway epithelial cells progressively lose their epithelial characteristics and acquire mesenchymal features, including increased vimentin and α-SMA expression. This process, heavily triggered by cigarette smoke, contributes to airway remodeling, fibrosis, inflammation, and tissue destruction through the generation of fibrotic stromal cells. Several signaling pathways—particularly Wnt family member (Wnt)/β-catenin, transforming growth factor-β (TGF-β), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)—are known to regulate this transition (11–15). However, the full spectrum of transcriptomic alterations associated with innate immune responses (16), upregulation of cytokines (17) and secretomes (10, 18), trained immunity (19–21), regulated cell death pathways (22, 23), and cell trans-differentiation (24), including epithelial-to-mesenchymal transition (EMT) and fibrosis remains incompletely defined.
The respiratory tract is constantly exposed to inhaled pathogens and toxic substances. Antigen-presenting cells (APCs) orchestrate innate and adaptive immune responses by processing and presenting antigenic peptides to T cells (25). Cigarette smoke reduces CD4+Foxp3+ regulatory T cells (Treg) populations, with significantly lower Treg frequencies are significantly lower, observed in smokers compared with non-smokers (26). Tregs play a central role in restraining pulmonary inflammation in COPD (27). We previously demonstrated that chronic exposure to cigarette smoke combined with morphine further decreases CD4+ Tregs through transcriptomic reprogramming (28) and promotes Treg plasticity toward a pro-inflammatory CD4+ T helper cell 17 (Th17) phenotype (29), in part via trained immunity mechanisms (30). Cigarette smoke also promotes inflammation through reactive oxygen species (ROS)-driven induction of trained immunity and trained tolerance mechanisms (31). Professional APCs—monocytes, macrophages, and dendritic cells—present antigenic peptides via major histocompatibility complex (MHC) molecules to CD4+ and CD8+ T cells (32, 33). Moreover, a range of non-professional APCs, including alveolar epithelial cells, endothelial cells (16, 34, 35), vascular smooth muscle cells (36), fibroblasts, innate lymphoid cells (ILCs), eosinophils, mast cells, and other interstitial cell populations, can express MHC class II and modulate CD4+ T cell activation and differentiation (25).
Given the centrality of T cell–APC interactions in immune regulation (37), immune checkpoint inhibitors have emerged as critical modulators and form the basis of modern cancer immunotherapies (37, 38). COPD is the most common comorbidity in lung cancer patients (39), and as immunotherapy extends survival, it becomes increasingly important to understand immune checkpoint expression and signaling in COPD. However, despite their relevance, immune checkpoint dysregulation in COPD remains poorly defined.
Taken together, several major gaps remain in our understanding of COPD immunopathology. Key unanswered questions include whether COPD induces transcriptomic reprogramming across the full spectrum of cytokines, chemokines, secretomes, plasma membrane proteins, CD markers, innate immune genes, and trained immunity; whether COPD alters regulators spanning all 14 known forms of regulated cell death; and whether master regulators of tissue remodeling—particularly EMT, fibrosis, and pathological trans-differentiation—are dysregulated. To address these gaps, we applied a novel, knowledge-based, multi-dimensional transcriptomic analysis platform to systematically interrogate molecular and cellular reprogramming in COPD. Here, we provide a comprehensive characterization of COPD-associated transcriptional dysregulation and uncover new mechanisms by which COPD transforms the lung into an immune organ.
2 Materials and methods
2.1 Transcriptomic data collection
To investigate gene expression changes and immunoregulatory pathways in COPD, we curated and analyzed publicly available transcriptomic datasets from the NIH-NCBI Gene Expression Omnibus (GEO) database.1 These datasets encompassed both human and mouse studies across multiple tissue types and experimental conditions relevant to lung inflammation, immune regulation, and COPD pathogenesis. The following datasets included: COPD lung tissue: whole-lung transcriptome from 11 COPD patients and 11 healthy controls (GSE239897); SET domain containing 7, histone lysine methyltransferase (SET7) knockout: H9 human embryonic stem cells transfected with SET7 siRNA (n = 2; GSE53038); Interleukin-37 (IL-37) overexpression: white adipose tissue from wild-type and human IL-37-overexpressing transgenic mice on a high-fat diet (GSE58952); alveolar macrophages from normal non-smokers (n = 24), normal smokers (n = 34), and smokers with COPD (n = 12) (GSE13896); poliovirus receptor (PVR) overexpression: CD4+ T cells stimulated with PVR-overexpressing L cells (n = 4, GSE194293); severe emphysema lung tissue: lungs from smokers with severe emphysema (n = 18) and mild/no emphysema (n = 12) (GSE1650); lipopolysaccharide (LPS)-stimulated macrophages: monocytes-derived macrophages treated with LPS (n = 3; GSE5099); FoxP3+ Tregs (n = 3; GSE164460); LPS-treated resolving lung Tregs (n = 3; GSE104088); T cell immunoreceptor with Ig and ITIM domains (TIGIT)+ Tregs (n = 2; GSE56299); IL-10 (an anti-inflammatory/immunosuppressive cytokine)-treated CD4+ T cells (n = 3; GSE17199 and GSE198963); IL-10–treated monocytes: peripheral blood mononuclear cells (PBMC)-derived monocytes treated with IL-10 (n = 3; GSE43700); LPS and IL-10 blocking antibody treatment: human monocyte-derived macrophages stimulated with LPS and IL-10 blocking antibody (n = 3; GSE181250); IL-10–stimulated monocyte-derived DCs (n = 3; GSE180761). All datasets were downloaded from the publicly accessible NIH-NCBI GEO portal (see text footnote 1). Each dataset was curated and pre-processed for downstream analysis. Differential gene expression analysis was conducted using the GEO2R tool,2 allowing statistical comparisons between experimental and control groups within each dataset. Genes with p-value < 0.05 and log2 fold change (log2FC) > 1 or < -1 were considered significantly differentially expressed.
2.2 Metascape pathway analysis
To assess the biological relevance of the differentially expressed genes, pathway enrichment analysis was conducted using Metascape3 as we reported (36, 40). Gene lists derived from transcriptomic comparisons were uploaded to Metascape for annotation and enrichment analysis across multiple curated databases, including Gene Ontology (GO), KEGG, and Reactome. An enrichment threshold of adjusted p-value < 0.01 was applied. The Metascape outputs were used to identify enriched biological processes, molecular functions, and signaling pathways related to immune regulation, cell death, fibrosis, EMT, and inflammation.
3 Results
3.1 COPD-induced inflammatory and innate immunity pathways
Cytokines are established mediators of chronic inflammation in COPD (2). We hypothesized that in COPD, the secretory proteins—including cytokines, chemokines, and secretomes (41)—may drive systemic inflammation and comorbidities. To investigate how COPD alters inflammatory and innate immune pathways, we analyzed bulk RNA-Seq dataset from lung tissue of COPD patients available in the NIH-NCBI-GEO database (GSE239897) (4, 42). We applied a knowledge-based transcriptomic profiling approach previously developed by our group (17, 19, 40) (Figure 1).
Figure 1. Workflow diagram of the study. Chronic Obstructive Pulmonary Disease (COPD) transcriptomic datasets were obtained from the National Institutes of Health (NIH). Differential gene expression analysis was performed using GEO2R, identifying significantly altered genes with a log2 fold change (log2FC) > 1 and P < 0.05. Subsequent analyses focused on genes associated with inflammation, immune response, pathological transdifferentiation, cell death, and lung injury. Additionally, loss-of-function and gain-of-function datasets were utilized to validate key findings and provide proof-of-concept for the involvement of trained immunity and immunosuppressive pathways in COPD progression.
As summarized in Table 1, COPD lungs demonstrated significant upregulation in the expression of 49 of 1,325 cytokine/chemokine genes (3.7%), 339 of 9,525 secretome genes (3.6%), 45 of 2,202 plasma membrane protein-encoding genes (2.04%), 24 of 384 CD marker genes (6.3%), 39 of 1,615 innate immune genes (2.4%), and six of 101 trained immunity genes (5.9%).
Table 1. Transcriptomic profiling identifies COPD-associated inflammatory, innate immune, and trained immunity gene signatures.
To explore the contribution of trained immunity, we assessed gene suppression SET7 (a promoter of trained immunity) knockout (SET7-KO) and IL-37 (an inhibitor of trained immunity) overexpression model—both known to interfere with trained immunity (43, 44). SET7-KO downregulated 58 of 426 COPD-upregulated genes (13.6%), while IL-37 overexpression suppressed 12 of these genes (2.8%). These finding suggest that trained immunity plays a significant role in COPD pathogenesis, consistent with earlier studies highlighting innate immunity’s role in COPD (45). Metascape pathway enrichment analysis identified significantly enriched pathways linked to each group of COPD-upregulated inflammatory and innate immune genes (Supplementary Table 1), with most pathways unique to specific gene sets—highlighting functional diversity. Collectively, the upregulation of cytokine, chemokine and secretome genes likely represent a central mechanism by which COPD promotes lung and bronchial inflammation, systemic inflammation and multiple comorbidities.
3.2 COPD-induced lung injury is associated with upregulation of genes involved in regulated cell death
It is well established that four forms of regulated cell death—apoptosis (46), necroptosis (47), pyroptosis (inflammatory cell death) (48), and ferroptosis (49)—contribute to the pathogenesis of COPD. In 2018, the International Nomenclature Committee on cell death classified 12 distinct forms of regulated cell death, including intrinsic and extrinsic apoptosis, mitochondrial permeability transition (MPT) cell death, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, neutrophil extracellular traps (NET)otic cell death, lysosome-dependent cell death (LDCD), autophagy-dependent cell death (ADCD), and immunogenic cell death (ICD) (50). We hypothesized that COPD may contribute to lung tissue injury by broadly upregulating genes associated with multiple regulated cell death pathways.
Transcriptomic analysis revealed that COPD significantly upregulated genes linked to all 12 forms of regulated cell death (Table 2). Specifically, we identified differential expression of 21 of 581 pyroptosis genes (3.6%), four of 346 apoptosis genes (1.2%), three of 239 necroptosis genes (1.3%), eight of 494 ferroptosis genes (1.6%), 35 of 1,831 autosis genes (1.9%), six of 359 autophagy genes (1.7%), four of 301 parthanatos genes (1.3%), 62 of 3,452 immunogenic cell death genes (1.8%), four of 204 MPT genes (2.0%), three of 233 lysosomal cell death genes (1.3%), 21 of 1,701 mitotic cell death genes (1.2%), and 31 of 1,782 proliferation-associated cell death genes (1.7%).
Table 2. COPD promotes diverse forms of programmed cell death.
Pathway enrichment analysis using Metascape (Supplementary Table 2) identified 43 significantly enriched pathways associated with the upregulated genes from the 12 regulated cell death categories. Notably, pyroptosis shared only a limited number of pathways with autosis, immunogenic cell death, mitotic cell death, and proliferation-associated cell death. In contrast, autophagy, parthanatos, ICD, and proliferation-associated cell death were largely characterized by distinct, non-overlapping pathway enrichments. Collectively, these findings demonstrate for the first time that COPD-induced lung injury involves not only the classical forms of cell death (apoptosis, necroptosis, pyroptosis, and ferroptosis), but also eight additional forms of regulated cell death, including autosis, autophagy-dependent cell death, parthanatos, immunogenic cell death, MPT-induced cell death, lysosomal-dependent cell death, mitotic cell death, and proliferation-associated cell death. This expanded our understanding of COPD pathogenesis and reveals novel mechanistic insights and suggests new potential therapeutic targets.
3.3 COPD promotes epithelial to mesynchymal transition and fibrosis
Lung fibrosis in COPD is increasingly recognized as a key pathological feature that contributes to small airway remodeling and progressive airflow limitation. In COPD, chronic inflammation, oxidative stress, and repeated epithelial injury promote fibroblast activation and extracellular matrix (ECM) deposition, leading to peribronchiolar fibrosis. This fibrotic remodeling narrows small airways, impairs lung elasticity, and often coexists with emphysematous destruction, together accelerating lung function decline (51, 52). Emerging evidence also suggests that specific molecular pathways such as EMT are central drivers of fibrosis in COPD (12). However, a comprehensive transcriptomic analysis specifically focused on defining the fibrotic landscape in COPD has not yet been conducted. To address this, we assessed transcriptomic changes in genes associated with EMT and fibrosis. As shown in Table 3, gene expression analysis revealed that COPD upregulates 36 of 1,153 EMT genes (3.12%) and 27 of 777 fibrosis-related genes (3.47%), while downregulated six EMT genes (0.52%), and ten fibrosis-related genes (1.29%). Metascape pathway analysis of these differentially expressed genes (Supplementary Table 3) identified significantly enriched pathways, with a dominant enrichment of proinflammatory signaling pathways.
Table 3. Chronic obstructive pulmonary disease (COPD) promotes epithelial-to-mesenchymal transition (EMT) and fibrotic remodeling in the lung.
COPD also modulated the gene expression of epithelial and mesenchymal genes where 259 of 5,769 epithelial cell genes (4.49%) and 26 of 901 mesenchymal cell genes (2.89%) were upregulated in COPD, COPD also downregulated 37 epithelial cell genes (0.64%) and ten mesenchymal cell genes (1.11%) (Supplementary Table 4). These findings indicate that COPD predominantly induces upregulations—rather than downregulation—of genes involved in epithelial and mesenchymal cell identity, while simultaneously promoting EMT and fibrosis. When integrated with data presented in Table 1, these results suggest that COPD promotes chronic inflammation, fibrogenesis, and tissue remodeling by reprogramming multiple cell types and activating inflammatory and profibrotic gene networks.
3.4 COPD induces lung tissue dysfunction through transcriptomic reprogramming and pathological trans-differentiation
We recently proposed that pathological trans-differentiation plays a critical role in the progression of chronic inflammation and cardiovascular diseases (24). In line with this concept, a recent single-cell RNA-Sequencing (scRNA-Seq) study by Sauler et al. (53) identified a subpopulation of alveolar epithelial type 2 (AT2) cells in COPD lungs with gene expression signatures indicative of metabolic dysregulation and impaired stress responses. The study also identified proinflammatory endothelial subtypes with increased CXCL chemokine signaling and macrophage subset enriched for metallothionein expression, particularly in advanced COPD. In support of these findings, other studies have documented the plasticity of lung epithelial cells in response to injury, such as the de-differentiation of secretory cells into basal cells and the capacity of Hopx+ alveolar type 1 (AT1) cells to generate AT2 following pneumonectomy (54). Based on this, we hypothesized that COPD alters the transcriptomes of multiple cell type-specific marker genes across diverse pulmonary cell populations. As illustrated in Figure 2A, the proportion of upregulated marker genes in COPD varied significantly across different lung cell types: 30.15% in respiratory ciliated cells, 23.53% in mast cells, 9.01% in B cells, 7.8% in T cells, 5.4% in plasma cells, 2.26% in AT1 cells, and 1.18% in fibroblasts. Using established methodologies (36, 55), we further examined cell type–specific gene expression across 81 human cell types curated by the Human Protein Atlas (HPA). As shown in Figure 2B, 52 of the 81 cell types demonstrated significant transcriptional upregulation in COPD lungs, with 18 showing more than a 5% increase in cell type–specific gene expression. These included ciliated cells, basal respiratory cells, club cells, ionocytes, mucus glandular cells, immune cell subsets (T cells, B cells, plasma cells, natural killer (NK) cells, granulocytes, and Langerhans cells), as well as non-respiratory cell types such as enterocytes, exocrine and breast glandular cells, pancreatic endocrine cells, and spermatogenic cells.
Figure 2. Chronic obstructive pulmonary disease (COPD) induces lung tissue damage, transcriptional reprogramming of resident cells, and pathological cell trans-differentiation. (A) Transcriptomic profiling demonstrated that COPD markedly alters the expression of cell-type–specific marker genes across 10 of 14 major human lung cell types. Increased marker expression was detected in respiratory ciliated cells, alveolar type I cells, B cells, mast cells, T cells, and plasma cells, whereas decreased expression was observed in alveolar type II cells, mitotic cells, and neutrophils. Cell-type–specific gene sets were obtained from the Human Protein Atlas (HPA). (B) COPD significantly increased the expression of cell-type–specific marker genes in 52 of 81 human cell types, with 18 cell types marked by * exhibiting > 5% marker gene enrichment. These included ciliated cells, basal respiratory cells, club cells, ionocytes, mucus glandular cells, proximal enterocytes, exocrine glandular cells, breast glandular cells, pancreatic endocrine cells, spermatocytes, early and late spermatids, T cells, B cells, plasma cells, NK cells, granulocytes, and Langerhans cells. (C) COPD promotes pathological cell trans-differentiation, likely through both direct injury-induced mechanisms and indirect inflammatory signaling, contributing to altered cellular identity and impaired tissue homeostasis.
Together, these results suggest that COPD triggers extensive transcriptomic reprogramming in 10 out of 14 major lung cell types, likely through both direct injury and indirect signaling pathways, potentially involving mesenchymal cell-mediated mechanisms (Figure 2C). This reprogramming is characterized by the widespread upregulation of cell type-specific markers, offering mechanistic insights into how COPD drives tissue dysfunction and pathological cell trans-differentiation.
3.5 COPD enhances immune responses by downregulating inhibitory and stimulatory immune checkpoint ligands on alveolar macrophages
Immune checkpoints, typically expressed on T cells and CD4+Foxp3+ Treg, and their corresponding ligands expressed on APCs, are critical membrane-bound regulators of immune homeostasis. These checkpoint pathways mediate essential cell-cell interactions between T cells (including Tregs) and APCs (32, 37, 56, 57). Immune checkpoint inhibitors have become standard-of-care therapy for various malignancies, particularly lung cancer, the most common comorbidity in patients with COPD (21). Additionally, emerging immunotherapies such as adoptive T cell strategies, including Treg-based treatments, are being explored for chronic respiratory diseases like severe asthma and COPD (58). Given this context, we hypothesized that COPD alters the expression of immune checkpoint ligands, particularly on alveolar macrophages. As shown in Table 4, COPD was associated with significant downregulation of 19 out of 51 known immune checkpoint ligands [curated in our recent review (37)] in alveolar macrophages of smokers with COPD (28, 30, 31) relative to healthy non-smokers. This included 11 inhibitory, seven stimulatory, and one dual-function ligand. When compared to healthy smokers, seven ligands were significantly downregulated in COPD (four inhibitory, two stimulatory, and one dual-function ligand). In contrast, the difference between healthy smokers and healthy non-smokers involving the downregulation of four inhibitory ligands, two stimulatory ligands, and one dual function ligand.
Table 4. Chronic obstructive pulmonary disease (COPD) may enhance immune activation by downregulating immune checkpoint ligand expression in alveolar macrophages.
These findings indicate that COPD results in a broader and more pronounced downregulation of inhibitory immune checkpoint ligand expression than stimulatory ones. This preferential loss of inhibitory signaling on alveolar macrophages may effectively “release the brakes” on immune activation, promoting exaggerated inflammatory responses in the lung and contributing to disease progression.
3.6 PVR (CD155) downregulation in lung tissue and alveolar macrophages in severe emphysema and COPD
Building on our recent comprehensive analysis of immune checkpoint receptor-ligand pairs in aortic diseases, which identified CD155 (poliovirus receptor, PVR) as key immunosuppressive ligands (38), and supported by emerging single-cell RNA sequencing studies highlighting a critical role for PVR in mediating immunosuppression within the tumor microenvironment (59), we hypothesized that PVR expression is similarly downregulated in progressive emphysema. To investigate this, we analyzed transcriptomic data from lung tissues of emphysema patients using the publicly available dataset GDS737. As shown in Figure 3A, PVR expression was significantly reduced in lung tissues from smokers with severe emphysema (n = 18) compared to those with mild or no disease (n = 12), suggesting that PVR loss may contribute to disease severity. Furthermore, analysis of alveolar macrophage transcriptomic profiles (GSE13896; log2FC > 1 and P < 0.05) revealed consistent patterns. PVR expression was significantly downregulated in alveolar macrophages from smokers with COPD (n = 12), showing a -1.124 log2FC compared to healthy non-smokers (n = 24) and -0.897 log2FC relative to healthy smokers (n = 34) (Figure 3B). Notably, PVR expression in alveolar macrophages from healthy smokers was not significantly altered relative to healthy non-smokers (0.555 log2FC). These data suggest that PVR downregulation in both lung tissue and alveolar macrophages is a COPD-specific phenomenon, potentially contributing to its inflammatory pathogenesis. Further mechanistic studies are warranted to explore the therapeutic relevance of targeting PVR.
Figure 3. Chronic obstructive pulmonary disease (COPD) downregulates the expression of the inhibitory immune checkpoint ligand poliovirus receptor (PVR/CD155) in emphysematous lung tissue and alveolar macrophages of COPD. (A) PVR expression was significantly reduced in lung tissue from smokers with severe emphysema (n = 18) compared to those with mild or no emphysema (n = 12), suggesting a potential role of PVR downregulation in the pathogenesis of COPD-related emphysema. Data were obtained from the NIH-NCBI GEO database (GSE1650). (B) PVR (CD155) expression was also significantly downregulated in alveolar macrophages from smokers with COPD relative to both normal non-smokers and normal smokers. No significant difference in PVR expression was observed between normal non-smokers and normal smokers, indicating that the reduction in PVR is specifically associated with COPD rather than smoking alone. **P < 0.01.
3.7 PVR overexpression suppresses proinflammatory gene expression in alveolar and interstitial macrophages in COPD
In addition to its immunosuppressive role through intercellular (outward) interaction with the immunosuppressive immune checkpoint receptor TIGIT (T cell immunoreceptor with Ig and ITIM domains) expressed on the plasma membranes of T cells and Treg, we hypothesized that PVR may also exert intracellular (inward) immunosuppressive effects within APCs such as macrophages. To explore this, we analyzed a multiple public transcriptomic datasets, including those from COPD lung tissues (GSE239897) (4), CD155-overexpression (CD4 T+ cells stimulated with CD155-expressing L cells) (GSE194293), alveolar macrophages from COPD patients (GSE13896) (60), and a smoking/COPD emphysema lung samples (GDS737) (61).
As summarized in Table 5, PVR overexpression significantly downregulated 13 genes that are upregulated in COPD lungs, 16 COPD-associated genes in sputum, 13 genes upregulated in healthy smokers, and 19 or 17 genes in COPD smokers (relative to healthy non-smokers or healthy smokers, respectively). These gene changes (log2FC > 1 and P < 0.05) suggest a broad anti-inflammatory effect of PVR.
Table 5. PVR (CD155) overexpression suppresses gene programs upregulated in chronic obstructive pulmonary disease (COPD).
Further analysis (Table 6) showed that PVR overexpression suppressed 49 proinflammatory genes expressed in CD14+IL-6Rhigh monocytes from lungs of COPD patients (GSE265853), which are key contributors to COPD exacerbation (60). Metascape pathway enrichment revealed these genes are involved in several biological pathways.
Table 6. PVR overexpression–mediated suppression of pro-inflammatory gene programs in CD14+IL-6Rhigh monocytes in COPD.
In addition, PVR overexpression significantly downregulated 76 genes associated with M1 (proinflammatory) macrophage polarization (M1 versus (vs.) M0), 14 genes associated with M2 (anti-inflammatory) macrophage polarization (M2 vs. M0), and 71 genes expressed more highly in M1 compared to M2 macrophages (M1 vs. M2). This yields an M1/M2 gene suppression ratio: 76/14 = 5.43, suggesting preferential inhibition of proinflammatory M1-associated gene expression. Pathway analysis revealed that 10 of the top 18 signaling pathways affected by PVR overexpression were associated with M1 macrophage genes. These included interferon-α/β signaling, type II interferon signaling, interleukin signaling, etc., which contrast with M2-associated pathways such as vitamin D receptor pathway and the negative regulation of cell-cell adhesion (Table 7).
Table 7. PVR overexpression modulates M1 and M2 macrophage polarization gene programs.
As shown in Table 8, COPD was associated with the upregulation of seven genes enriched in interstitial macrophages (IMs) relative to alveolar macrophages (AMs) (62), three genes elevated in small IMs compared to small AMs, and three genes specific to large AMs. Conversely, among genes classified as “COPD downregulated,” AMs exhibited higher expressions of IL-1R2 and IL-18R1 compared to IMs, while small AMs expressed higher levels of IL-1R2, S100A8, and S100A9 compared to large AMs. Moreover, COPD-AMs showed increased expression of ten genes (so-called “downregulation in IMs”), including NLRP3 (NOD-like receptor protein 3) (48), CCL20 (C-C motif chemokine ligand 20), INHBA (inhibin subunit beta A), ICAM1 (intercellular adhesion molecule 1), IL-1β (interleukin-1β) (63), IL18R1, IL1A, CXCL1 (C-X-C Motif Chemokine Ligand 1) (64), SERPINE1 (Serpin family E member 1), and TJP1 (Tight Junction Protein 1) in AMs compared to IMs, upregulation of four genes (so-called “downregulation in small IMs”), including CCL20, ICAM1, IGF1 (insulin like growth factor 1), and CXCL1 in small AMs compared to small IMs, and upregulation of seven genes (so-called “downregulation in large IMs”), including NLRP3, CCL5, CXCL5, INHBA, ICAM1, IL1A, and HGF (hepatocyte growth factor) in small AMs compared to large AMs. PVR overexpression was found to suppress the expression of eight genes in IMs including IL-1RL1 (interleukin 1 receptor like 1), MUC1 (Mucin 1, cell surface associated), CLDN1 (Claudin 1), IL-1A, VEGFA (vascular endothelial growth factor A), OAS1 (2’-5’-Oligoadenylate Synthetase 1), CCL20, and IL-13; three genes in small IMs such as IL-1L1, VEGFA, and CCL20; eight genes in large AMs, including IL-1RL1, MUC1, IFIH1 (interferon induced with helicase C domain 1), IL-1A, VEGFA, IRF7 (interferon regulatory factor 7), MX1 (MX dynamin like GTPase 1), and SERPINA1. Together, these findings demonstrate that PVR exerts potent anti-inflammatory effects across alveolar and interstitial macrophage subsets in COPD, supporting its role as a central immunoregulatory checkpoint in lung inflammation. These findings highlight PVR as a promising therapeutic target for modulating macrophage-driven inflammation in chronic lung diseases.
Table 8. COPD upregulated genes enriched in interstitial macrophages (IMs) and alveolar macrophage (AM) subsets, including: 4 IM-over-AM genes, 5 small IM-over-small AM genes, 2 large AM-specific genes, and 1 small AM-specific gene, while downregulating 1 small AM gene.
3.8 COPD weakens immunosuppressive Tregs by altering the transcriptional profiles of distinct Treg gene subsets
According to the World Health Organization, cigarette smoking is the leading cause of COPD.4 Previous studies have demonstrated a significant reduction in CD4+CD25+FoxP3+ Tregs in smokers compared to non-smoker healthy controls, suggesting impaired Treg-mediated immunosuppression in COPD. Through RNA-sequencing analysis, we have previously shown that both cigarette smoke and its combination with morphine profoundly alter Treg transcriptomes (28, 30, 31). Based on these findings, we hypothesized that COPD modifies the transcriptomic landscape of CD4+Foxp3+ Tregs, contributing to functional impairment. Our transcriptomic analysis (Table 9 and Supplementary Figures 1A–E) revealed that COPD upregulates 19 and downregulates six human Treg genes from the HPA database.
Table 9. COPD alters the transcriptional landscape of distinct regulatory T cell (Treg) subsets.
Furthermore, our analysis of previously published mouse Treg RNA-Seq dataset from a 2-month cigarette smoke exposure model (28, 30, 31) revealed that COPD upregulated eight genes previously identified as “smoke-upregulated” Treg genes and 55 of Treg inhibited genes “smoke-downregulated” Treg genes. These 55 genes are associated with Treg weakening, consistent with the hypothesis that COPD promotes Treg dysfunction and persistent inflammation. COPD also upregulated 19 and downregulated five Foxp3+ Treg-specific genes, including BIRC5, OSGIN1, IL-1R2, SPOCK2, and TTN (Titin). Furthermore, COPD downregulated four lipopolysaccharide (LPS)-responsive genes in lung Tregs—HMOX1, CLEC4E, IL-1R2, and F2RL3—which are involved in antimicrobial immunity. In addition, six TIGIT + Treg genes—CCDC41, FKBP5, HMOX1, IL-1R2, SPOCK2, and IL-18R1 were downregulated in COPD, indicating compromised immunosuppressive function.
The biological significances of these downregulated Treg genes have been previously described: BIRC5 (survivin) is upregulated in superTregs, which are more immunosuppressive than defective Treg and promote superTreg proliferation (65). OSGIN1 (Oxidative stress induced growth inhibitor 1) is a signature marker of tissue-resident memory T cells (Trm) (66). IL-1R2 acts as a decoy receptor that attenuates Treg activation (67). SPOCK2 (SPARC (Osteonectin), Cwcv and Kazal like domains proteoglycan 2) interact with Foxp3 to facilitate Treg communication (68). TTN, regulate T lymphocyte trafficking (69). HMOX1 (Heme oxygenase 1), induced by Foxp3, is essential for Foxp3+ Treg-mediated immune suppression (70). CLEC4s (C-type lectin domain family 4 member E) expression is positively correlated with immune cell infiltration (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) (71). F2RL3 (F2R like thrombin or trypsin receptor 3) modulates CD25, CD62L, and CD73 expression, Treg stability, and suppressive function through phosphorylation of FoxO1 and negative regulation of PTEN and FoxP3 (72). CCDC41 (Centrosomal Protein 83) also known as Cep83 is involved in membrane contact site formation during ciliogenesis and is required for cytotoxic T lymphocyte secretion, potentially facilitating Treg migration and secretion (73). FKBP5 (FKBP prolyl isomerase 5) has been linked to Treg dysfunction; high levels of FKBP51s+ Tregs were observed in non-responders to prototypic immunosuppressive immune checkpoint cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockade (ipilimumab), suggesting impaired CTLA-4 signaling in these cells (74), suggesting that FKBP5 may decrease the expression of CTLA4 and present a CTLA4 signaling weakening. IL-18R1 (Interleukin 18 receptor 1) is critical for Foxp3+ Treg cell-mediated control of inflammation, where it promotes the expression of key Treg effector molecules (75). After removing redundant entries, we identified 11 unique Treg-specific genes (BIRC5, OSGIN1, IL-1R2, SPOCK2, TTN, HMOX1, CLEC4E, F2RL3, CCDC41, FKBP5, and IL-18R1) consistently downregulated in COPD. These results support the hypothesis that COPD-induced transcriptional reprogramming of Tregs contributes to their dysfunction, thereby facilitating chronic pulmonary inflammation.
3.9 COPD weakens the functions of Treg, and other cell-secreted immunosuppressive cytokine IL-10 by downregulating IL-10-induced immunosuppressive genes
It has been reported that COPD progression is associated with elevated serum levels of the proinflammatory cytokine IL-17 and reduced levels of anti-inflammatory cytokines IL-10 and IL-35 (76). IL-10, like IL-35, plays a crucial role in immune tolerance and supports Treg function in the COPD lung environment (77). We hypothesized that COPD impairs the function of IL-10—secreted by Treg and other immune cell—by modulating IL-10-induced transcriptional responses. To test this hypothesis, we analyzed five publicly available datasets from the NCBI-GEO database. As shown in Table 10 and Supplementary Figures 2A–E, in the CD4+ T cell stimulated with IL-10 (GSE17199) dataset, COPD upregulated 16 IL-10-induced genes in CD4+ T cells, suggesting compensatory activation of IL-10 pathways during inflammation. Nevertheless, COPD also upregulated nine IL-10–suppressed genes and downregulated three IL-10-induced genes such as TRIB3 (Tribbles pseudokinase 3), DDIT4 (DNA damage inducible transcript 4), and PSAT1 (phosphoserine aminotransferase 1). In a second IL-10-treated CD4+ T cell dataset (GSE198963), COPD similarly downregulated RIPOR3 (RIPOR family member 3), another IL-10–upregulated gene and reversed the repression of five genes suppressed by IL-10. We then explored IL-10 regulation in innate immune cells in COPD, we analyzed a transcriptomic dataset of IL-10-treated monocytes (GSE43700) and found that IL-10 downregulated 29 COPD-upregulated genes and upregulated 11 COPD upregulated genes, including GLT1D1 (glycosyltransferase 1 domain containing 1), TRIB3, HK3 (Hexokinase 3), SIGLEC16 (sialic acid binding Ig like lectin 16), HMOX1, P2RY1 (purinergic receptor P2Y1), SLCO4A1 (solute carrier organic anion transporter family member 4A1), CD163, DDIT4, PSAT1, and SIGLEC10 (sialic acid binding Ig like lectin 10). These genes are enriched in metabolic and homeostatic pathways, highlighting IL-10’s role in immunometabolic regulation—disrupted in COPD.
Table 10. IL-10 Counteracts COPD-associated proinflammatory gene expression across multiple immune cell types.
To further elucidate IL-10-regulated transcriptional programs in macrophages relevant to COPD, we analyzed a transcriptomic dataset, in which human monocyte-derived macrophages were primed with macrophage colony-stimulation factor (M-CSF), stimulated with LPS, and subsequently treated with an IL-10 blocking antibody (GSE181250). IL-10 inhibition upregulated 23 COPD-upregulated genes, suggesting these genes may be normally suppressed by IL-10 under homeostatic conditions. COPD also downregulated three IL-10 blocking downregulated (IL-10 promoted) genes such as FKBP5 (FK506-binding protein prolyl isomerase 5), SLCO4A1, and HMOX1, indicating that IL-10 may promote their expressions in healthy macrophage responses. We also analyzed a transcriptomic dataset of monocyte-derived DC stimulated with IL-10 (GSE180761). IL-10 suppressed 24 COPD-upregulated genes, while COPD downregulated 13 IL-10-upregulated genes, including GLT1D1 (glycosyltransferase 1 domain containing 1), BIRC5, HK3, HMOX1, OSGIN1, LOC105377771, IL-18R1, KIF2C (kinesin family member 2C), SLCO4A1, CD163, SPOCK2, SIGLEC11, and S100A9 (S100 calcium binding protein A9).
Pathway enrichment analysis of these overlapping genes revealed significant association with RHO GTPase effector signaling, Leishmania infection, and inflammatory response pathways, underscoring the immunoregulatory role of IL-10 in counteracting inflammatory gene expression programs that are dysregulated in COPD (Supplementary Figures 2A–E).
Taken together, our data have demonstrated that: first, anti-inflammatory cytokine IL-10 modulates the transcriptomes of monocytes, macrophages and DCs in COPD more than that in CD4+ T cells; second, some IL-10 upregulated genes are induced in COPD, suggesting that IL-10 pathways are responsive to COPD inflammation induction; third, COPD downregulates some IL-10 pathways genes, suggesting that COPD weakens IL-10 signaling for disease progression; and fourth, IL-10 inhibits some COPD upregulated genes, suggesting that IL-10 fulfills its anti-inflammatory and immunosuppressive functions in COPD.
3.10 PVR overexpression shares immunosuppressive gene signature with IL-10 in CD4+ T cells and myeloid cells
We hypothesized that the immunosuppressive function of PVR (CD155) may partially overlap with IL-10-mediated transcriptional programs in both CD4+ T cells and myeloid cells. To assess this hypothesis, we conducted a comparative transcriptomic analysis using publicly available datasets obtained from the NCBI-GEO database. In CD4+ T cells (Table 11 and Supplementary Figures 3A–E), no genes were commonly upregulated by both PVR overexpression and IL-10 stimulation, indicating distinct activation programs. However, six genes upregulated by PVR were downregulated by IL-10, and 21 genes downregulated by PVR were upregulated by IL-10. These findings highlight divergent regulatory effects exerted by PVR and IL-10 in CD4+ T cells. Despite this divergence, nine genes—IL-1A, YPEL5 (Yippee like 5), TRANK1 (tetratricopeptide repeat and Ankyrin repeat containing 1), ZBP1 (Z-DNA Binding Protein 1), MX2 (MX Dynamin Like GTPase 2), IFI6 (interferon alpha inducible protein 6), HERC5 (HECT and RLD domain containing E3 ubiquitin protein ligase 5), PDK1 (Pyruvate Dehydrogenase Kinase 1), and DHX58 (DExH-box helicase 58)—were consistently downregulated by both PVR overexpression and IL-10 stimulation, suggesting convergence on shared immunosuppressive targets. Pathway enrichment analysis of these shared genes revealed significant involvement in antiviral defense responses and cytokine-mediated signaling in the immune system, supporting a potential role for both IL-10 and PVR in dampening proinflammatory and antiviral transcriptional programs in T cells.
Table 11. PVR overexpression in CD4+ T cells partially recapitulates IL-10–mediated immunosuppressive transcriptional programs across multiple immune cell types.
We extended our analysis by examining a second IL-10 treated CD4+ T cells (GSE198963) to compare gene expression overlaps with PVR-overexpressing CD4+ T cells. Only a single gene, SLC27A2, was found to be upregulated by both PVR and IL-10. In contrast, 28 genes downregulated by PVR overlapped with genes upregulated by IL-10, and eight genes—TAGAP-AS1 (TAGAP antisense RNA 1), PCSK6 (proprotein convertase subtilisin/Kexin type 6), TAGAP (T cell activation RhoGTPase activating protein), BHLHA15 (basic helix-loop-helix family member A15), RHOB (Ras homolog family member B), PKD1L3 (polycystin 1 like 3, transient receptor potential channel interacting), SESN2 (Sestrin 2), and N4BP3 (NEDD4 binding protein 3) were downregulated by both PVR and IL-10, further supporting a partially shared immunosuppressive transcriptional profile.
To investigate this relationship in innate immune cells, we compared the transcriptomic data from PVR-overexpressing CD4+ T cells with IL-10-stimulated monocytes (GSE43700). Among the overlapping genes, four were upregulated by both PVR and IL-10, while 15 were upregulated by PVR but downregulated by IL-10. Strikingly, 78 genes downregulated by PVR overlapped with genes upregulated by IL-10, and 77 PVR-downregulated genes also overlapped with IL-10-downregulated genes. These bidirectional overlaps suggest that PVR and IL-10 may regulate a common set of immunoregulatory genes, either in parallel or in opposing directions depending on the cellular context. Pathway enrichment analysis of the 77 overlapping genes highlighted involvement in interferon alpha/beta signaling, modulation of host response by IFN-stimulated genes, and other immune regulatory pathways. Further supporting the idea of functional convergence, monocyte derived macrophages stimulated with LPS and IL-10 blocking antibody (GSE181250) shows that 39 genes downregulated by PVR in CD4+ T cells were also upregulated upon IL-10 inhibition, suggesting shared immunosuppressive targets between PVR overexpression in T cells and IL-10 stimulated monocytes. These genes were enriched in pathways including inflammatory bowel disease signaling, positive regulation of cell migration, regulation of cell-cell adhesion, Fas ligand pathway and stress induction of heat shock proteins, overview of proinflammatory and profibrotic mediators, and other inflammation pathways (Supplementary Figure 3D). Conversely, 24 genes downregulated by PVR also overlapped with genes downregulated upon IL-10 blockade (IL-10 promoted genes), further reinforcing a shared immunosuppressive transcriptional axis between PVR and IL-10. Finally, monocyte derived DC cell stimulated with IL-10 (GSE180761) demonstrates substantial overlaps between PVR-downregulated genes in CD4+ T cells and IL-10-regulated genes in DCs: 57 PVR-downregulated genes overlapped with IL-10-downregulated genes, while 111 overlapped with IL-10-upregulated genes. Pathway enrichment analysis of the 57 overlapped downregulated genes indicated associations with pathways such as positive regulation of monoatomic ion transport, neovascularization process, regulation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 cascade (Supplementary Figure 3E).
Taken together, these results indicate that PVR overexpression in CD4+ T cells share a significant number of immunosuppressive genes and signaling pathways with IL-10–mediated responses across multiple immune cell types—including CD4+ T cells, monocytes, and dendritic cells. While substantial transcriptional overlap suggests a shared functional program, distinct gene expression signatures also emerge, underscoring that PVR and IL-10 regulate both overlapping and unique components of immune suppression.
4 Discussion
In this study, we present a comprehensive transcriptomic analysis that delineates the molecular and cellular mechanisms by which COPD drives lung inflammation, injury, and immune dysregulation: Our findings reveal several major themes: (1) COPD promotes the upregulation of cytokines, secretomic proteins, plasma membrane proteins, CD markers, innate immune genes, and trained immunity genes. Notably, the suppression of the trained immunity promoter SET7 and overexpression of IL-37 reduces the expression of 58 and 12 COPD-upregulated genes, respectively, highlighting their potential as anti-inflammatory regulators. (2) COPD-induced lung injury is associated with the transcriptional upregulation of genes across eight distinct forms of cell death, including autosis, autophagy, parthanatos, immunogenic cell death, mitochondrial permeability transition cell death, lysosomal cell death, mitotic cell death, and proliferation-associated cell death, in addition to the four classical cell death pathways—including pyroptosis, apoptosis, necroptosis, and ferroptosis, reflecting widespread cellular stress and damage. (3) COPD significantly alters the transcriptional landscape in 10 out of 14 human lung cell types. Differentially expressed genes were upregulated in respiratory cilliated cells, alveolar cells type I, B cells, fibroblasts, mast cells, T cells, and plasma cell. Importantly, we observed pathological trans-differentiation, with upregulation of 52 cell-type-specific markers, including 18 markers with expression exceeding 5% of total cell-type-specific marker genes —indicating broad shifts in cell identity and function. (4) COPD upregulate genes associated with EMT and fibrosis. These changes suggest sustained activation of proinflammatory, profibrotic, and remodeling pathways. (5) In alveolar macrophages from smokers with COPD, we observed significant downregulation of 11 inhibitory, 7 stimulatory, and one dual-function immune checkpoint ligands, indicating broad dysregulation of immune checkpoint signaling. (6) The inhibitory immune checkpoint ligand PVR (CD155) was significantly downregulated in alveolar macrophages from patients with severe emphysema and COPD, suggesting impaired immunosuppressive signaling in the lung microenvironment. (7) Functional analysis showed that overexpression of PVR in alveolar and interstitial macrophages suppressed the expression of 12 genes —including IL-1RL1, MUC1, CLDN1, IL1A, VEGFA, OAS1, CCL20, IL-13, IFIH1, IRF7, MX1, and SERPINA1—highlighting its potential role in regulating macrophage-mediated inflammation in COPD. (8) We found significant transcriptional reprogramming of Tregs in COPD, with downregulation of 74 Treg-related genes across multiple gene sets, including six from the HPA, 55 smoke-sensitive genes, five FoxP3+ Treg genes, four LPS-responsive lung Treg genes, and 5 TIGIT+ Treg genes, these changes indicate a weakening of Treg-mediated immune tolerance. (9) COPD lungs showed downregulation of 31 genes normally upregulated by IL-10, suggesting impaired IL-10–mediated anti-inflammatory signaling in the COPD lung environment. (10) Among 190 genes downregulated by PVR overexpression in CD4+ T cells, a substantial number overlapped with IL-10–inhibited genes in CD4+ T cells and monocytes. This convergence suggests that PVR and IL-10 may operate through overlapping immunosuppressive pathways, which are disrupted in COPD.
Our additional analyses (Supplementary Figure 4) demonstrate that COPD is associated with a consistent reduction in the expression of key Treg immunosuppressive genes across both human disease samples and murine COPD models. By presenting differential expression data for canonical Treg markers, including FOXP3, TIGIT, and IL-10, we show that the observed suppression reflects a reproducible transcriptional trend rather than isolated gene-specific effects. These findings support the concept that chronic inflammatory conditions in COPD are accompanied by impaired Treg-mediated immune regulation, which may contribute to sustained immune activation and disease progression. Importantly, to further strengthen and extend these observations, we are currently performing RNA sequencing on lung tissues from COPD and cigarette smoke–exposed samples. Upon completion, these datasets will enable more refined transcriptomic analyses and facilitate experimental validation of Treg-associated gene dysregulation, providing an independent confirmation of our findings and allowing deeper mechanistic interrogation in future studies.
Our data support a model (Figure 4) in which environmental and microbial stimuli—such as cigarette smoke, air pollution, and DAMPs/PAMPs—drive widespread transcriptomic reprogramming in the lung. These changes include the upregulation of genes encoding plasma membrane proteins (e.g., CD markers), cytokines, chemokines, and secretomes. This dysregulated gene expression landscape promotes multiple forms of cell death, fibrotic remodeling, and pathological trans-differentiation of resident lung cell types. We also identified transcriptomic changes associated with antigen presentation dysfunction (APD) and altered expression of immune checkpoint ligands and receptors. Additionally, our findings indicate a compromised immunosuppressive function of regulatory T cells (Tregs) within the COPD lung microenvironment.
Figure 4. Proposed working model and summary of findings.
Although numerous studies have described cellular and inflammatory alterations in COPD, how EMT–associated transcriptional programs operate within specific cellular contexts to drive disease progression remains incompletely understood. In this study, our goal was not to assign causality at the single-cell or functional level, but rather to perform a transcriptomic, hypothesis-generating analysis aimed at identifying reproducible and biologically grounded EMT signatures associated with COPD. Importantly, the EMT gene sets analyzed here were not arbitrarily selected; they comprise well-established, experimentally validated EMT-associated genes derived from extensive prior research. Leveraging these curated gene lists enables a knowledge-driven transcriptomic framework that complements, rather than replaces, cell-resolved approaches and differs conceptually from automated pathway tools by anchoring interpretation in established biology. Consistent with prior reports demonstrating a contributory role for EMT in COPD pathogenesis (11–13, 78), our findings provide additional mechanistic hypotheses by highlighting coordinated EMT-related transcriptional changes at the tissue level. These data should therefore be interpreted as candidate molecular programs that are likely to reflect altered epithelial plasticity and remodeling in COPD, which will require validation through spatially resolved transcriptomics and targeted functional assays. Such studies, which we plan to pursue pending additional funding, will be essential to define how EMT-associated pathways function within discrete lung cell populations to promote structural remodeling and disease progression.
Together, these changes suggest that the COPD lung adopts characteristics of an immune-endocrine organ, sustaining chronic airway inflammation, promoting tissue destruction and remodeling, and ultimately driving disease progression. Furthermore, these local changes may contribute to systemic inflammation observed in COPD patients, underscoring the multisystemic impact of the disease.
In summary, our integrative transcriptomic analysis reveals that COPD orchestrates a complex network of cellular and molecular events involving immune activation, epithelial and endothelial remodeling, induction of diverse cell death programs, and disruption of key immunoregulatory mechanisms. Notably, we identify a novel convergence between the inhibitory checkpoint molecule PVR and the anti-inflammatory cytokine IL-10, both of which are downregulated in COPD and share overlapping immunosuppressive gene targets. These findings suggest that the loss of PVR and IL-10–mediated signaling contributes to the chronic inflammation and immune dysregulation characteristic of COPD. Moreover, the observed transcriptional reprogramming of regulatory T cells, professional antigen-presenting cells, and structural lung cells underscores the systemic nature of COPD pathogenesis. Collectively, this study provides a comprehensive molecular framework for understanding COPD progression and identifies potential therapeutic targets—such as SET7, IL-37, PVR, and IL-10—for restoring immune balance and limiting lung damage in COPD patients.
Data availability statement
The data analyzed in this study are publicly available and were obtained from the NIH Gene Expression Omnibus (GEO) repository. The accession numbers for all datasets used are provided in the manuscript. No new datasets were generated in this study.
Author contributions
FS: Software, Methodology, Investigation, Data curation, Visualization, Conceptualization, Validation, Writing – original draft, Writing – review & editing, Formal analysis. KX: Formal analysis, Conceptualization, Writing – review & editing. YL: Formal analysis, Conceptualization, Writing – review & editing. YS: Conceptualization, Writing – review & editing, Formal analysis. BH: Conceptualization, Writing – review & editing, Formal analysis. XW: Conceptualization, Formal analysis, Writing – review & editing. XJ: Conceptualization, Formal analysis, Writing – review & editing. XL: Formal analysis, Writing – review & editing, Conceptualization. JD: Writing – review & editing, Formal analysis, Conceptualization. HW: Formal analysis, Supervision, Writing – review & editing, Conceptualization. BK: Formal analysis, Supervision, Writing – review & editing, Funding acquisition, Conceptualization, Resources. XY: Funding acquisition, Visualization, Supervision, Formal analysis, Project administration, Writing – original draft, Data curation, Writing – review & editing, Conceptualization.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported in part by the NIH grant HL163570-01A1 (XY), and by the DoD grant W81XWH2110414 (BK).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2026.1721780/full#supplementary-material
Footnotes
1. ^https://www.ncbi.nlm.nih.gov/gds
2. ^https://www.ncbi.nlm.nih.gov/geo/geo2r/
3. ^https://metascape.org/gp/index.html#/main/step1
4. ^https://www.who.int/news/item/15-11-2023-smoking-is-the-leading-cause-of-chronic-obstructive-pulmonary-disease
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Keywords: COPD, epithelial-to-mesenchymal transition (EMT), immune organs, secretomes, trained immunity
Citation: Saaoud F, Xu K, Lu Y, Shao Y, Han B, Wang X, Jiang X, Liu X, Du J, Wang H, Kosmider B and Yang X (2026) Chronic obstructive pulmonary disease reprograms the lung into an immune organ through trained immunity, cell death networks, and immune checkpoint dysregulation. Front. Med. 13:1721780. doi: 10.3389/fmed.2026.1721780
Received: 09 October 2025; Revised: 22 December 2025; Accepted: 05 January 2026;
Published: 28 January 2026.
Edited by:
Harry Karmouty Quintana, University of Texas Health Science Center at Houston, United StatesReviewed by:
Nirmal Parajuli, Henry Ford Health System, United StatesGerard Hoyne, University of Notre Dame Australia, Australia
Copyright © 2026 Saaoud, Xu, Lu, Shao, Han, Wang, Jiang, Liu, Du, Wang, Kosmider and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiaofeng Yang, eGZ5YW5nQHRlbXBsZS5lZHU=; Beata Kosmider, YmVhdGEua29zbWlkZXJAdGVtcGxlLmVkdQ==