Nuclear Protein Induces Anti-Inflammatory Gene Expression in Sepsis.

Expansion and accumulation of Myeloid-Derived Suppressor Cells (MDSCs) during sepsis contribute to post-sepsis immunosuppression, as these cells suppress innate and adaptive immunity. We have shown that the proinflammatory protein accumulates in the nucleus of MDSCs during late sepsis in both mice and humans. In this context, nuclear acts as a transcription co-factor to induce the expression of two potent immunosuppressive cytokines, Interleukin-10 (IL-10) and Transforming Growth Factor-β (TGF-β). knockdown in MDSCs from late septic mice and late septic patients significantly reduced IL-10 and TGF-β production upon stimulation with bacterial lipopolysaccharide. In contrast, ectopic expression of in MDSCs from -deficient mice significantly increased IL-10 and TGF-β production. Chromatin immunoprecipitation revealed that protein binds at the IL-10 and TGF-β promoters. Moreover, co-transfection of expression plasmid with a luciferase reporter gene under the control of IL-10 or TGF-β promoter induced the luciferase gene expression in MDSCs from -deficient mice. Notably, in vivo depletion of long noncoding Ribonucleic Acid (RNA) , which induces protein accumulation in MDSCs during late sepsis, reduced IL-10 and TGF-β production . Since IL-10 and TGF-β enhance sepsis immunosuppression and are associated with worse outcomes, our findings suggest that targeting may mitigate the immunosuppressive effects of MDSCs in late sepsis.