MEF2 intervened LPS-induced acute lung injury by binding to KLF2 promoter and modulating macrophage phenotype

Transcription factor myocyte enhancer factor 2 (MEF2) exerts anti-inflammatory activities in endothelial cells, yet its role in acute lung injury (ALI) remains unclear. Homeostasis dysfunction in macrophage polarization is essential for the pathogenesis of ALI. Kruppel-like factor 2 (KLF2) and microRNA-33 (miR-33), important regulators in macrophage polarization, have been predicted as the downstream and upstream modulator of MEF2, respectively. This study aimed to investigate the function of MEF2 in ALI and its regulatory mechanism on macrophage polarization. Murine ALI models were established by intratracheal instillation of 5 mg/kg lipopolysaccharide (LPS) for 24 h. M1-type macrophage polarization was induced with LPS and interferon gamma, while the M2-type one was induced with interleukin-4 for 24 h in vitro. In ALI murine models, pulmonary MEF2 and KLF2 expressions were decreased. MEF2 and KLF2 expressions were higher in M2 macrophages than those in M1 macrophages in vitro. Conversely, microRNA-33 level was higher in M1 macrophages. Our study firstly demonstrated that MEF2 could increase M2 polarization but inhibit M1 polarization of macrophages in vitro and its overexpression mitigated LPS-induced ALI, increased pulmonary KLF2 expression and drove alveolar macrophage polarization from an M1 to an M2 phenotype in vivo. MEF2 was confirmed to bind to KLF2 promoter. Moreover, MEF2 regulated macrophage phenotypes via KLF2. In addition, miR-33 could bind to MEF2 and inhibit MEF2 expression in macrophages. It was speculated that miR-33 might be implicated in macrophage polarization through inhibiting MEF2 expression. Taken together, MEF2 may be a novel target for treating ALI.