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PPAR-γ alleviates Streptococcus pneumoniae -induced airway epithelial injury by promoting monocyte-derived macrophage to alveolar macrophage transformation

developmental-biology
microbiology
molecular-biology
immunology
pathology

Abstract

Alveolar macrophages (AMs), the primary immune effector cells in the pulmonary parenchyma, play a critical role in maintaining alveolar homeostasis, defending against pathogens, and regulating inflammatory responses. Our previous studies demonstrated that neonatal Streptococcus pneumoniae infection induces airway epithelial injury, though the molecular mechanisms remain incompletely understood. Bioinformatics analysis of the public dataset GSE225406 identified PPAR-γ and the PPAR signaling pathway as key regulators in the transformation of monocyte-derived macrophages (mMs) into AMs. In vivo experiments showed that neonatal S. pneumoniae infection significantly reduced AM and Club cell populations, along with PPAR-γ expression. These pathological changes were alleviated by treatment with rosiglitazone (RSG), a PPAR-γ agonist. To investigate the mechanisms by which PPAR-γ promotes Club cell regeneration and function, we co-cultured 16HBE cells with isolated primary AMs. PPAR-γ-activated AMs enhanced the proliferation and migration of 16HBE cells, potentially through increased secretion of placenta-expressed transcript 1 (Plet1). Collectively, these findings reveal a novel mechanism in which S. pneumoniae infection suppresses PPAR-γ transcriptional activity, thereby impairing mM-to-AM transformation, reducing Plet1 release, and ultimately hindering Club cell regeneration. These insights suggest that PPAR-γ activation may offer a therapeutic strategy for S. pneumoniae-induced airway epithelial injury.
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