Figure 8. A model for sepsis-induced myelopoiesis and generation of MDSCs.

During the immune response to sepsis, inflammatory cytokines such as IL-6 and IL-10, and bacterial endotoxins induce expression the of C/EBPβ, which synergizes with Stat3 to activate the miR-21 and miR-181b promoters in the Gr1⁺CD11b⁺ myeloid progenitors. The miRNAs then induce NFI-A expression, which attenuates the cell differentiation and maturation via decreasing p21, increasing cdk4, and decreasing PTEN protein levels (not shown). These persistently activate the NF-kB and thus accelerate myelopoiesis and expand numbers of Gr1⁺CD11b⁺ cells. During the early phase of sepsis, these cells are immunocompetent like Gr1⁺CD11b⁺ cells generated under steady-state conditions. During the late phase, Gr1⁺CD11b⁺ cells are reprogrammed into the immunosuppressive phenotype, i.e., MDSCs. The myeloid cell-specific knockout of C/EBPβ blocks this process during sepsis and thus prevents immunosuppression.