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

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.