Dataset Information

PPAR-γ Suppresses Macrophage Senescence and Allergic Airway Inflammation through Controlling Lipid Metabolic Pathways

ABSTRACT: Background: Cellular senescence has emerged as a key contributor to the pathogenesis of chronic lung diseases. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear transcription factor, regulates senescence across multiple cell types. However, the role of PPAR-γ in allergic airway inflammation, particularly through regulation of macrophage senescence, remains poorly defined. Methods: Cellular senescence was evaluated in an allergic asthma mouse model using single-cell RNA sequencing (scRNA-seq). Senescent cells were selectively eliminated with dasatinib and quercetin (D&Q) to assess their contribution to disease pathogenesis. Macrophage-lineage-specific PPAR-γ conditional knockout model (PpargΔCD11c) were generated to define the role of macrophage PPAR-γ in senescence and allergic airway inflammation. PPAR-γ activity was further examined in isolated alveolar macrophages and in vivo using rosiglitazone, including macrophage-targeted delivery via phosphatidylserine-modified liposomes (PSL-ROSI). Findings: scRNA-seq analysis revealed enhanced senescence signatures in mononuclear phagocytes (MNPs), characterized by increased SenMayo scores and elevated Cdkn2a (p16) expression. Clearance of senescent cells significantly reduced airway inflammation and Th2 cytokine levels (IL-4, IL-5). Correlation analysis identified PPAR-γ as a key transcriptional regulator inversely associated with cellular senescence. Macrophage-lineage–specific deletion of PPAR-γ (PpargΔCD11c) exacerbated airway inflammation and increased cellular senescence. In vitro, rosiglitazone reduced allergen-induced senescence and suppressed proinflammatory mediators (IL-6, ICAM-1, CCL4, CCL5, TIMP-1, TNF-α) in alveolar macrophages. In vivo, rosiglitazone and inhaled PSL-ROSI attenuated cockroach allergen-induced airway inflammation, with PSL-ROSI effectively bypassing the airway mucus barrier to deliver rosiglitazone to lung macrophages. Integrated chromatin binding and transcriptomic analyses demonstrated that PPAR-γ promotes macrophage lipid metabolic programs (e.g., CD36, Fabp4). Interpretation: These findings identify macrophage senescence as a pathogenic driver of allergic airway inflammation and establish PPAR-γ as a critical regulator of macrophage senescence and homeostasis, highlighting its potential as a therapeutic target for asthma.

ORGANISM(S): Mus musculus

PROVIDER: GSE322708 | GEO | 2026/03/16

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Inflammatory bowel disease (IBD) is a condition characterized by severe intestinal inflammation and immune cell activation. The severity of the disease can be mitigated by compounds which activate peroxisome proliferator-activated receptor gamma (PPAR gamma), a receptor present widely in tissues involved in IBD pathogenesis. Our objective was to assess the affect of macrophage-specific deficiency of PPAR gamma on peripheral and colonic immune populations and colonic gene expression in experimental IBD. Macrophage-specific PPAR gamma-deficient mice (PPAR gamma flfl Lysozyme M Cre+) and control (PPAR gamma flfl Lysozyme M Cre-) littermates were treated with 2.5% dextran sodium sulfate (DSS) for 7 days. Disease activity was recorded daily and immune cell populations in the blood, spleen, mesenteric lymph nodes (MLN), and lamina propria were examined by flow cytometry. Colonic gene expression was assessed by real time PCR and microarray analyses. Our findings show that macrophage PPAR r-deficiency significantly exacerbates DSS inflammation. CD4+CD25+FoxP3+ regulatory T cells (T-regs) were significantly reduced in Cre+ mice, and MLN macrophages and CD40 expression were enhanced. There were significant differences in the number colonic macrophages between Cre+ and Cre- mice, but those from Cre+ mice expressed more CD40, Ly6C, and TLR-4. PPAR r-deficiency also increased the percent of CD8+ T cells in the lamina propria and enhanced colonic interferon gamma expression. Our findings indicate that macrophage PPAR gamma deficiency augments the severity of DSS colitis by reducing peripheral T-regs and increasing colonic macrophage activation and T cell inflammation. RNA from 3 PPAR gamma-deficient mice (PPAR gamma flfl; Lysozyme M Cre+) and 3 control (PPAR gamma flfl; Lysozyme M Cre-) littermates was processed and labeled according to the standard target labeling protocols. The samples were hybridized, stained, and scanned per standard Affymetrix protocols at the Virginia Bioinformatics Institute (VBI) core laboratory on Mouse 430 2.0 expression arrays (Affymetrix Inc., Santa Clara, CA).

Project description:Background: Environmental allergens can induce epithelial cellular senescence, which contributes to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may regulate this process. Objectives: We sought to determine whether epithelial AhR controls cellular senescence and to define its underlying mechanisms in allergic airway inflammation. Methods: Club cell-specific p16 conditional knockout mice (p16ΔScgb1a1) were used to assess the role of epithelial senescence and allergic airway inflammation. AhR regulation of senescence was examined using AhR agonist, antagonist, and Club cell-specific AhR-deficient mice (AhRΔScgb1a1) in both in vitro and in vivo models. Bulk RNA-seq was performed to identify AhR-regulated, senescence-associated genes, and immunoprecipitation (IP) along with ChIP-PCR was employed to validate AhR-target gene interactions. Results: Single-cell transcriptomics revealed epithelial senescence as a key feature of allergen-induced asthma. p16ΔScgb1a1 mice exhibited reduced cockroach allergen–induced airway inflammation and decreased Th2/Th17 cytokines in bronchoalveolar lavage fluids (BALFs). AhR signaling was enhanced in airway epithelial cells of allergen-treated asthmatics and regulated senescence, as indicated by SA-β-gal activity and expression of Cdkn2a, Cdkn1a, and γH2AX. The AhR agonist VAF347 suppressed, whereas AhRΔScgb1a1 deficiency exacerbated, airway inflammation. RNA-seq identified senescence as a major AhR-regulated pathway, highlighting c-Myc, TGF-β2, IGFBP3, and SERPINE1 as key targets. AhR binding to the c-Myc promoter was validated, and c-Myc inhibition with EN4 reduced allergen-induced senescence and inflammation. Conclusions: Epithelial AhR suppresses allergen-induced senescence and airway inflammation through direct regulation of c-Myc. These findings establish the AhR–c-Myc axis as a potential therapeutic target in allergic asthma.

Dataset Information

PPAR-γ Suppresses Macrophage Senescence and Allergic Airway Inflammation through Controlling Lipid Metabolic Pathways

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets