Chromatin Regulator SRG3 Overexpression Protects against LPS/D-GalN-Induced Sepsis by Increasing IL10-Producing Macrophages and Decreasing IFNγ-Producing NK Cells in the Liver

Abstract

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3β-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3β-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3β-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.

Ferroptosis in Macrophage Impairment in Sepsis

“…Generally speaking, macrophages can be classified according to their function and activation, i.e., M1 (classical activation) or M2 (alternative activation), but the time point at which macrophages differentiate into M1 type macrophages and M2 type macrophages is not clear. M1 macrophages are mainly composed of lipopolysaccharide (LPS) and/or interferon γ (interferon γ ), tumor necrosis factor α (tumor necrosis factor α ), and other cytokines [ 10 – 12 ]. M2 macrophages are mainly composed of IL-4 and transforming growth factor β (transforming growth factor β ) and immune complex induced activation [ 13 ].…”

Identifying Six Chromatin Remodeling-related Genes As Diagnostic Biomarkers in Sepsis Using Bioinformatic Analyses

“…SIRT6, which regulates chromatin remodeling, genome stability, and transcription, was shown to regulate mitochondrial dynamics and biogenesis and induce G 2 /M cell cycle arrest, both of which are related to the pathophysiology of sepsis [9] . Overexpression of SWItch3-related gene, a chromatin remodeling factor, promoted the differentiation of M2 macrophages and suppressed the production of interferon-γ by natural killer (NK) cells, which positively in uenced the prognosis of sepsis [10] . These studies suggest that chromatin remodeling-related genes (CRRGs) play important roles in sepsis and may emerge as new potential therapeutic targets for this disease.…”

Macrophage polarization in cesarean scar diverticulum

“…induced alternate activation of macrophages (M2 macrophages) [9]. Other M2 phenotypes can be induced by MCSF and IL-10 [10]. Uterine wound repair is generally characterized as an inflammatory and wound-healing response, where these two phenotypes of macrophages are dominant [11].…”

“…The two classic macrophages include typically activated macrophages (M1 macrophages) induced by LPS and IFN-γ, and Th2 cytokines, such as IL-4 and IL-13 induced alternate activation of macrophages (M2 macrophages)[9]. Other M2 phenotypes can be induced by MCSF and IL-10[10]. Uterine wound repair is generally characterized as an inflammatory and wound-healing response, where these two phenotypes of macrophages are dominant[11].…”