ITE-mediated AhR activation attenuates atherosclerosis by promoting macrophage M2-like polarization through...

Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid accumulation and inflammation. Macrophage phenotypic transformation plays a critical role in AS progression. Aryl hydrocarbon receptor (AhR) has been proved to regulate the phenotype of macrophages. This study investigates the role and molecular mechanism of AhR activation by its endogenous ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) attenuates AS.

We employed Western blotting to analyze the expression of AhR, NF-κB, and lipocalin-2 (LCN2). Flow cytometry and immunofluorescence staining were used to assess the phenotype of macrophages. Plaque progression was evaluated using pathological staining. Transcriptome sequencing was utilized to explore the potential mechanism by which AhR promotes macrophage phenotypic transformation. CUT&Tag-qPCR and lentivirus infection confirmed that the AhR/NF-κB/LCN2 pathway regulates macrophage polarization.

Activation of AhR by ITE reduced plaque area and inhibited lipid deposition. ITE significantly increased the number of M2-like macrophages both in vivo and in vitro. Transcriptome sequencing identified LCN2 as a key target for AhR-mediated macrophage M2-like polarization. Furthermore, AhR activation suppressed the NF-κB/LCN2 pathway.

Our findings reveal that AhR promotes the macrophages to exhibit M2-like characteristics to attenuate AS by inhibiting the NF-κB/LCN2 pathway. These results suggest that AhR may serve as a novel therapeutic target for AS.