Novel pharmacological inhibition of EZH2 attenuates septic shock by altering innate inflammatory responses to sepsis.
Int Immunopharmacol
; 76: 105899, 2019 Nov.
Article
em En
| MEDLINE
| ID: mdl-31518916
ABSTRACT
The function of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in sepsis remains unknown. We reported here that the expression of EZH2 and H3K27me3 was significantly upregulated in the circulation of septic patients, whereas patients who survived presented downregulated the expression of EZH2 on CD14+ monocytes. We further identified increased expression of EZH2 in the circulation, peritoneal fluid, and septic lungs from CLP mice. 3-DZNeP treated CLP mice improved mortality and protected from organ injury. EZH2 inhibition not only suppressed the activation of inflammatory cells and release of cytokines in the circulation and infectious sites, but also promoted bacteria clearance and replenished the circulating monocyte and neutrophil pool from bone marrow. Blockage of EZH2 also suppressed the progression of lung injury and alleviated inflammation by decreasing the pulmonary cell apoptosis, reducing inflammatory cells infiltration and cytokines release through inhibition of the STAT3 signaling pathway and recovery of PPARγ activation. In addition, EZH2 inhibitor blunted macrophage M1 polarization by SOCS3/STAT1 pathway. Overall, these data suggest that EZH2 could be a potential biomarker predicting clinical outcome and a new target for therapeutic interference in sepsis.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
Proteína Potenciadora do Homólogo 2 de Zeste
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China