Expression of C/EBPβ in myeloid progenitors during sepsis promotes immunosuppression

Sepsis-induced myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression associated with sepsis. We reported that the CCAAT enhancer-binding protein C/EBP beta activates microRNA (rniR)-21 and miR181b expressions, which induce transcription factor NFI-A to support the generation and expansion of MDSCs in the bone marrow and spleens of septic mice. Here, using a conditional knockout mouse model lacking C/EBP beta in the myeloid lineage, we find that without C/EBP beta, myeloid progenitor cells could not express miR-21 or miR181b, and ectopic expression of C/EBP beta in the C/EBP beta-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBP beta-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBP beta. Exogenous expression of miR-21 and miR-181b in the C/EBP beta-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kappa B MDSC generating pathway was reversed in the C/EBP beta-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBP beta expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.