RRC ID 82678
Author Phuengmaung P, Khiewkamrop P, Makjaroen J, Issara-Amphorn J, Boonmee A, Benjaskulluecha S, Ritprajak P, Nita-Lazar A, Palaga T, Hirankarn N, Leelahavanichkul A.
Title Less Severe Sepsis in Cecal Ligation and Puncture Models with and without Lipopolysaccharide in Mice with Conditional Ezh2-Deleted Macrophages (LysM-Cre System).
Journal Int J Mol Sci
Abstract Despite a previous report on less inflammatory responses in mice with an absence of the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, using a lipopolysaccharide (LPS) injection model, proteomic analysis and cecal ligation and puncture (CLP), a sepsis model that more resembles human conditions was devised. As such, analysis of cellular and secreted protein (proteome and secretome) after a single LPS activation and LPS tolerance in macrophages from Ezh2 null (Ezh2flox/flox; LysM-Crecre/-) mice (Ezh2 null) and the littermate control mice (Ezh2fl/fl; LysM-Cre-/-) (Ezh2 control) compared with the unstimulated cells from each group indicated fewer activities in Ezh2 null macrophages, especially by the volcano plot analysis. Indeed, supernatant IL-1β and expression of genes in pro-inflammatory M1 macrophage polarization (IL-1β and iNOS), TNF-α, and NF-κB (a transcription factor) were lower in Ezh2 null macrophages compared with the control. In LPS tolerance, downregulated NF-κB compared with the control was also demonstrated in Ezh2 null cells. In CLP sepsis mice, those with CLP alone and CLP at 2 days after twice receiving LPS injection, representing sepsis and sepsis after endotoxemia, respectively, symptoms were less severe in Ezh2 null mice, as indicated by survival analysis and other biomarkers. However, the Ezh2 inhibitor improved survival only in CLP, but not LPS with CLP. In conclusion, an absence of Ezh2 in macrophages resulted in less severe sepsis, and the use of an Ezh2 inhibitor might be beneficial in sepsis.
Volume 24(10)
Published 2023-5-10
DOI 10.3390/ijms24108517
PII ijms24108517
PMID 37239864
PMC PMC10218384
MeSH Animals Endotoxemia* / genetics Enhancer of Zeste Homolog 2 Protein / genetics Epigenesis, Genetic Humans Ligation Lipopolysaccharides Macrophages / metabolism Mice Mice, Knockout NF-kappa B / metabolism Proteomics Punctures Sepsis* / genetics Sepsis* / metabolism Tumor Necrosis Factor-alpha / metabolism
Resource
Mice RBRC02302 RBRC05555