Ursolic acid promotes microglial polarization toward the M2 phenotype via PPARγ regulation of MMP2 transcription

Abstract

Microglia, which are the primary inflammatory cells of the brain, can undergo phenotypic switching between M1 and M2 polarization, which have opposing effects on inflammation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear receptor family of ligand-inducible transcription factors, and PPARγ is known to regulate M2 macrophage polarization. Previous studies have shown that the natural pentacyclic triterpenoid ursolic acid (3β-hydroxy-urs-12-en-28-oic acid; UA) influences microglial activation. Additionally, UA increases tissue inhibitor matrix metalloproteinase 1 (TIMP1), while greatly reducing the release of matrix metalloproteinase 2 (MMP2) and MMP9 in a PPARγ-dependent manner. Here, we examined the anti-inflammatory properties of UA by observing how well it promotes the phenotypic transition of lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated BV2 microglia from M1 to M2 polarization. To determine if PPARγ is involved in the underlying molecular pathway, we treated rats with UA and the PPARγ inhibitor BADGE. We also investigated the mechanisms by which PPARγ controls transcription from the MMP2 promoter. The in-vitro experiments showed that UA shifted LPS/IFNγ-activated BV2 microglia from the M1 to the M2 phenotype, which was associated with a reduction in the neurotoxic factors MMP2 and MMP9, and an increase in the anti-inflammatory factor TIMP1. Co-treatment with increased MMP2 and MMP9 synthesis while decreasing TIMP1 release, indicating that UA has anti-inflammatory effects on LPS/IFNγ-activated BV2 cells via activation of PPARγ. Next, we found that PPARγ directly influences MMP2 transcriptional activity by identifying the crucial peroxisome proliferator response element (PPRE) among five potential PPREs in the MMP2 promoter. These results suggest that UA has a protective anti-inflammatory effect against neuroinflammatory toxicity, which is exerted by direct activation of PPARγ and selectively modulates microglial polarization and suppresses MMP2 formation.

Keywords: M2 phenotype; Matrix metalloproteinase; Microglia; Peroxisome proliferator-activated receptor gamma; Ursolic acid.