Glimepiride Modulates LPS-Induced M1 Macrophage Polarization <i>via</i> PPAR<i>γ</i>-Mediated Inhibitory Mechanism

This research intended to explore the role of glimepiride, a sulfonylurea-class medication, in regulating macrophage polarization and clarify its underlying molecular mechanism. In vitro experiments were performed using a lipopolysaccharide (LPS)-induced M1 polarization model in the murine macrophage cell line RAW264.7. Different concentrations (low, medium, and high) of glimepiride were applied to evaluate their effects on the expression of M1 macrophage-specific markers. Transcriptome sequencing was conducted to identify potential regulatory pathways. Small interfering RNA (siRNA) was used to silence target genes, aiming to verify the impacts on downstream signaling pathways and pro-inflammatory cytokine secretion. In vitro experiments revealed that glimepiride markedly suppressed LPS-induced M1 macrophage polarization and diminished the expression levels of M1-specific markers, encompassing cluster of differentiation 86 (CD86) and inducible nitric oxide synthase (iNOS). Transcriptomic profiling indicated that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway was modulated by glimepiride. Functional verification via PPARγ siRNA knockdown revealed that glimepiride mediated its regulatory effects by suppressing the expression of phosphorylated inhibitor of nuclear factor kappa B (IκB)/p65, which in turn restrained M1 macrophage polarization and attenuated pro-inflammatory cytokine release. These findings demonstrate that glimepiride inhibits M1 macrophage polarization through a PPARγ-dependent blockade of the IκB-p65 signaling pathway. This study highlights a novel anti-inflammatory mechanism of glimepiride, providing preclinical evidence for its potential application in anti-inflammatory therapies.