Sepsis-induced immunosuppression increases the risk of chronic infection and reduces survival. Myeloid-derived suppressor cells (MDSCs) expand in the bone marrow and spleen during murine polymicrobial sepsis, contributing to immunosuppression. A better understanding of molecular controls of MDSC production is needed to identify treatment targets. We previously reported that miR-21 and miR-181b couple with transcription factor NFI-A to induce MDSCs during murine sepsis. Here, we expand upon these observations by showing that conditional deletion of the Nfia gene in the myeloid lineage precludes MDSC development. NFI-A-deficient Gr1+CD11b+ myeloid cells are not immunosuppressive and differentiate normally into macrophages and dendritic cells. In contrast, ectopically expressed NFI-A prevents differentiation of these immature Gr1+CD11b+ cells, while converting them into MDSCs. In addition, NFI-A-deficient Gr1+CD11b+ cells decreased, and cells transfected with NFI-A increase expression of miR-21 and miR181b. Our results support a myeloid cell loop in which NFI-A and miR-21 and miR-181b sustain Gr1+CD11b+ MDSC-dependent immunosuppression during sepsis.
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Dai, Jun; Kumbhare, Ajinkya; Williams, Danielle A.; Youssef, Dima; Yao, Zhi Q.; McCall, Charles E.; and Gazzar, Mohamed El. 2018. Nfia Deletion in Myeloid Cells Blocks Expansion of Myeloid-Derived Suppressor Cells During Sepsis. Innate Immunity. Vol.24(1). 54-65. https://doi.org/10.1177/1753425917742956 PMID: 29172874 ISSN: 1753-4259