EZH2 contributes to sepsis-induced acute lung injury through regulating macrophage polarization

Abstract

Background

Zeste enhancer homolog 2 (EZH2) is a pivotal regulator of gene dynamics implicated in the progression of sepsis-induced acute lung injury (SALI). EZH2 regulates aberrant inflammatory and immune responses in macrophages via unconventional biochemical interactions. However, the mechanisms driving atypical behavior of EZH2 during sepsis remain elusive, and therapeutic strategies targeting EZH2 are currently underutilized.

Purpose

This study aimed to investigate how EZH2 regulates macrophage polarization through the AKT pathway to improve SALI and to explore therapeutic drugs targeting EZH2.

Methods

We used Western blotting, hematoxylin-eosin stainin, immunofluorescence, flow cytometry, qRT-PCR, RNA sequencing, and chromatin immunoprecipitation sequencing methods to investigate regulation of macrophage immune response by EZH2 and explored its specific mechanism. These methods were also used to examine the protective effects of MS177 against SALI.

Results

Specific deletion of EZH2 in macrophages reduced the level of AKTIP, downregulated the M1 macrophage markers CD86 and cytotoxic T cell marker CD8+, upregulated the M2 macrophage marker CD206 and regulatory T cell marker FOXP3+, decreased the levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-β, and increased the level of anti-inflammatory cytokine IL-10. This ultimately improved lung injury and mortality in SALI mice. EZH2 promoted the M1 polarization of macrophages by activating AKT2 via direct binding to the promoter region of AKTIP in a SALI mouse model. Furthermore, MS177 alleviated SALI by degrading EZH2 both in vitro and in vivo.

Conclusion

EZH2 regulates macrophage polarization via the AKTIP-AKT2 pathway. Our findings suggest that MS177 is a promising therapeutic agent for EZH2-dependent SALI.