Background Cellular senescence has emerged as a key contributor to the pathogenesis of chronic lung diseases. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a nuclear transcription factor, regulates senescence across multiple cell types. However, the role of PPAR-gamma 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-gamma conditional knockout model (Pparg Delta CD11c) were generated to define the role of macrophage PPAR-gamma in senescence and allergic airway inflammation. PPAR-gamma 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), characterised 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-gamma as a key transcriptional regulator inversely associated with cellular senescence. Macrophage-lineage-specific deletion of PPAR-gamma (Pparg Delta CD11c) 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-alpha) 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-gamma 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-gamma as a critical regulator of macrophage senescence and homoeostasis, highlighting its potential as a therapeutic target for asthma.
[1]Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Baltimore, MD USA.
[2]Soochow Univ, Childrens Hosp, Dept Resp Med, Suzhou, Jiangsu, Peoples R China.
[3]Wannan Med Coll, Dept Pulm & Crit Care Med, Affiliated Hosp 1, Wuhu, Anhui, Peoples R China.
[4]Cent South Univ, Xiangya Hosp 2, Dept Resp Med, Changsha, Hunan, Peoples R China.
[5]Johns Hopkins Univ, Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD USA.
[6]Johns Hopkins Univ, Dept Orthopaed Surg, Sch Med, Baltimore, MD USA.
(8.0+极速模式)