Glimepiride Modulates LPS-Induced M1 Macrophage Polarization via PPARγ-Mediated Inhibitory Mechanism

Area of Science:

• Immunology
• Pharmacology

Background:

• Macrophage polarization plays a critical role in inflammatory responses.
• M1 macrophages are pro-inflammatory, and their dysregulation contributes to various diseases.
• Glimepiride, a sulfonylurea, is primarily used for type 2 diabetes.

Purpose of the Study:

• To investigate the effect of glimepiride on macrophage polarization.
• To elucidate the molecular mechanisms underlying glimepiride's action on M1 macrophages.

Main Methods:

• Used lipopolysaccharide (LPS) to induce M1 polarization in RAW264.7 macrophages.
• Treated cells with varying concentrations of glimepiride.
• Performed transcriptome sequencing and siRNA-mediated gene silencing (PPARγ, IκB/p65).
• Assessed M1 markers (CD86, iNOS) and pro-inflammatory cytokine secretion.

Main Results:

• Glimepiride significantly suppressed LPS-induced M1 polarization and reduced M1 marker expression.
• Transcriptomic analysis identified the peroxisome proliferator-activated receptor gamma (PPARγ) pathway as a key target.
• PPARγ knockdown confirmed glimepiride's mechanism involves inhibiting the IκB/p65 signaling pathway.
• Glimepiride attenuated pro-inflammatory cytokine release.

Conclusions:

• Glimepiride inhibits M1 macrophage polarization via a PPARγ-dependent blockade of the IκB-p65 pathway.
• This study reveals a novel anti-inflammatory role for glimepiride.
• Provides preclinical evidence for glimepiride's potential in anti-inflammatory therapies.