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/EBPβ activates microRNA (miR)-21 and miR-181b 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/EBPβ in the myeloid lineage, we find that without C/EBPβ, myeloid progenitor cells could not express miR-21 or miR-181b, and ectopic expression of C/EBPβ in the C/EBPβ-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBPβ-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBPβ. Exogenous expression of miR-21 and miR-181b in the C/EBPβ-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kB MDSC generating pathway was reversed in the C/EBPβ-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBPβ expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.
Dai, Jun; Kumbhare, Ajinkya; Youssef, Dima; Yao, Zhi Q.; McCall, Charles E.; and El Gazzar, Mohamed. 2017. Expression of C/EBPβ in Myeloid Progenitors During Sepsis Promotes Immunosuppression. Molecular Immunology. Vol.91 165-172. https://doi.org/10.1016/j.molimm.2017.09.008 PMID: 28934717 ISSN: 0161-5890