| First Author | Alkhateeb T | Year | 2019 |
| Journal | Mol Immunol | Volume | 112 |
| Pages | 72-81 | PubMed ID | 31078118 |
| Mgi Jnum | J:344771 | Mgi Id | MGI:6879054 |
| Doi | 10.1016/j.molimm.2019.04.019 | Citation | Alkhateeb T, et al. (2019) S100A9 maintains myeloid-derived suppressor cells in chronic sepsis by inducing miR-21 and miR-181b. Mol Immunol 112:72-81 |
| abstractText | Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPbeta synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1(+)CD11b(+) cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPbeta protein complex that activates the miRNA promoters. Reconstituting Gr1(+)CD11b(+) cells from S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPbeta protein complex and miRNA expressions, and switches the Gr1(+)CD11b(+) cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b. |
