The PPARγ Agonist Rosiglitazone Modulates Macrophage Inflammatory Responses in a Klebsiella pneumoniae Infection Model

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates lipid metabolism, cell differentiation, proliferation, apoptosis, and inflammatory responses. Emerging evidence implicates PPARγ as a therapeutic target for modulating dysregulated inflammation in sepsis. Klebsiella pneumoniae, a Gram-negative encapsulated bacterium of the Enterobacteriaceae family, has evolved enhanced pathogenicity through acquisition of antimicrobial resistance (AMR) genes, posing a critical threat in healthcare settings, particularly among immunocompromised and hospitalized patients. This study aimed to characterize the role of PPARγ, its interactions with downstream signaling proteins, and its capacity to modulate activation of differentiated primary bone marrow-derived macrophages (BMDMs) during K. pneumoniae infection in vitro.Differentiated BMDMs were infected with K. pneumoniae and treated with the PPARγ agonist rosiglitazone. Production of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO), expression of arginase-1 (arg-1), and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway were assessed. K. pneumoniae infection induced significant increases in TNF-α and NO production, arg-1 expression, and p38 MAPK pathway activation in BMDMs. Rosiglitazone treatment attenuated TNF-α and NO production, inhibited p38 MAPK activation, and further upregulated arg-1 expression in K. pneumoniae-stimulated BMDMs. These findings demonstrate that pharmacological activation of PPARγ by rosiglitazone modulates the inflammatory response of BMDMs during K. pneumoniae infection, suppressing pro-inflammatory mediators while promoting arg-1 expression. This supports the potential of PPARγ agonists as adjunctive therapeutic strategies for managing bacterial infections characterized by dysregulated inflammation and antimicrobial resistance in preclinical and clinical settings.