Stat3 and C/EBPβ Synergize to Induce miR-21 and miR-181b Expression During Sepsis

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Myeloid-derived suppressor cells (MDSCs) increase late sepsis immunosuppression and mortality in mice. We reported that microRNA (miR) 21 and miR-181b expression in Gr1 + CD11b + myeloid progenitors increase septic MDSCs in mice by arresting macrophage and dendritic cell differentiation. Here, we report how sepsis regulates miR-21 and miR-181b transcription. In vivo and in vitro binding studies have shown that C/EBPα transcription factor, which promotes normal myeloid cell differentiation, binds both miRNA promoters in Gr1 + CD11b + cells from sham mice. In contrast, in sepsis Gr1 + CD11b + MDSCs miR-21 and miR-181b promoters bind both transcription factors Stat3 and C/EBPβ, which co-imunoprecipitate as a single complex. Mechanistically, transcription factor Rb phosphorylation supports Stat3 and C/EBPβ accumulation at both miRNA promoters, and C/EBPβ or Stat3 depletion by siRNA in sepsis Gr1 + CD11b + MDSCs inhibits miR-21 and miR-181b expression. To further support this molecular path for MDSC accumulation, we found that Stat3 and C/EBP binding at miR-21 or miR-181b promoter was induced by IL-6, using a luciferase reporter gene transfection into naive Gr1 + CD11b + cells. Identifying how sepsis MDSCs are generated may inform new treatments to reverse sepsis immunosuppression.