gw-3965 and Sepsis

The defective eradication of invading pathogens is a major cause of death in sepsis. As professional phagocytic cells, macrophages actively engulf/kill microorganisms and play essential roles in innate immune response against pathogens. Growth differentiation factor 3 (GDF3) was previously implicated as an important modulator of inflammatory response upon acute sterile injury. In this study, administration of recombinant GDF3 protein (rGDF3) either before or after CLP surgery remarkably improved mouse survival, along with significant reductions in bacterial load, plasma pro-inflammatory cytokine levels, and organ damage. Notably, our

Topics: Animals; Benzoates; Benzylamines; Cells, Cultured; Cytokines; Gene Expression; Gene Expression Profiling; Growth Differentiation Factor 3; Liver; Liver X Receptors; Macrophages; Mice; Mice, Inbred C57BL; Phagocytosis; RAW 264.7 Cells; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sepsis

Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs.. Cecal ligation and puncture(CLP)was used to induce sepsis in mice. The mice were then treated with LXR agonist GW3965 (3 mg/kg) or vehicle 1 h, 6 h, 12 h, 24 h, 48 h, 72 h postoperatively. The effect of LXR on the survival rate and multi-organ injury induced by sepsis was evaluated by survival analysis, histological staining, biochemical analysis and ELISAs. The percentages of MDSCs and T cells were detected using flow cytometry. The mRNA expressions of LXR and ATP-binding cassette transporter A1 (ABCA1) were measured using real-time quantitative PCR (RT-qPCR). ABCA1 protein level was determined using immunofluorescence staining.. LXR agonist GW3965 treatment improved the survival of septic mice, accompanied by reduced multi-organ injury and a decreased level of inflammatory cytokines. Furthermore, GW3965 treatment decreased MDSCs abundance in spleen by boosting the apoptosis of spleen MDSCs, therefore ameliorating their immunosuppressive activity. Meanwhile, bacteria clearance in tissues was enhanced after the GW3965 administration in septic mice. Mechanistically, GW3965 activated LXRβ and its downstream target ABCA1 to initiate the apoptosis of spleen MDSCs.. These findings provide new insights into the relationship between LXR and MDSCs in sepsis, thus revealing a potentially effective approach to target the immunosuppression of sepsis.

Topics: Animals; Apoptosis; ATP Binding Cassette Transporter 1; Benzoates; Benzylamines; Cytokines; Liver X Receptors; Male; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Protective Agents; Sepsis