Hotairm1 Controls S100A9 Protein Phosphorylation in Myeloid-Derived Suppressor Cells during Sepsis.

During the acute phase of sepsis, the S100A9 proinflammatory protein resides in the cytosol in a phosphorylated form. In contrast, S100A9 relocalizes to the nucleus in an unphosphorylated form during the late/chronic sepsis state of immunometabolic paralysis. We reported that Hotairm1, a long noncoding RNA, facilitates S100A9 nuclear location in myeloid-derived suppressor cells. Here, we show that Hotairm1 promotes S100A9 nuclear location by limiting its phosphorylation by p38 MAPK. Knockdown of Hotairm1 in MDSCs from mice and humans with late sepsis increases phospho-S100A9 protein. Conversely, increasing Hotairm1 in early sepsis Gr1⁺CD11b⁺ cells by transfection decreases phospho-S100A9 protein levels. Notably, increasing S100A9 protein phosphorylation in late sepsis MDSCs via Hotairm1 knockdown decreases the production of the immunosuppressive cytokine IL-10. These results suggest that targeting Hotairm1 might reduce MDSC expansion during sepsis and thus relieve immunosuppression and improve survival.