MiR-146a-5p-enriched exosomes inhibit M1 macrophage activation and inflammatory response by targeting CD80.

Abstract

Background: Previous studies have demonstrated that miR-146a-5p negatively regulated the intrinsic immune and inflammatory responses, whether the miR-146a-5p-enriched exosomes possess the anti-inflammation effect remains unclear. This study aimed to investigate the effect of miR-146a-5p-enriched exosomes on M1 macrophage activation and inflammatory response and the potential molecular mechanism.

Methods: GEO database was used to analyze the expression of miR-146a-5p in serum exosomes of MASH patients. MiR-146a-5p levels in primary hepatocytes, macrophages, and serum exosomes of MASH mice were measured. MiR-146a-5p-enriched exosomes were constructed and the effects on M1 macrophages activation and inflammatory factors release were investigated. The target gene of miR-146a-5p was predicted and verified.

Results: Serum exosomal miR-146a-5p level was decreased in MASH patients analyzed by GEO database. The miR-146a-5p levels in primary cultured hepatocytes and macrophages of MASH mice were decreased. Serum exosomal miR-146a-5p level was decreased and negatively correlated with the concentrations of IL-6 in MASH mice. Furthermore, miR-146a-5p-enriched exosomes inhibited the M1 macrophages activation and the expression of pro-inflammatory factors MCP-1, IL-6, and TNF-α. CD80 was predicted as the potential target gene of miR-146a-5p, and the expression of CD80 was regulated by miR-146a-5p. In addition, the inhibitory effect of miR-146a-5p on M1 macrophages activation and inflammatory factors release was restored when CD80 was over-expressed.

Conclusions: This study demonstrated that miR-146a-5p-enriched exosomes can inhibit the M1 macrophages activation and reduce the release of pro-inflammatory factors by targeting CD80.