IL-10 Induces an Immune Repressor Pathway in Sepsis by Promoting S100A9 Nuclear Localization and MDSCdsc Development
The myeloid-related protein S100A9 reprograms Gr1+CD11b+ myeloid precursors into myeloid-derived suppressor cells (MDSCs) during murine sepsis. Here, we show that the immunosuppressive cytokine IL-10 supports S100A9 expression and its nuclear localization in MDSCs to function as immune repressors. To support this new concept, we showed that antibody mediated IL-10 blockade in wild-type mice after sepsis induction inhibited MDSC expansion during late sepsis, and that ectopic expression of S100A9 in Gr1+CD11b+ cells from S100A9 knockout mice switched them into the MDSC phenotype only in the presence of IL-10. Knockdown of S100A9 in MDSCs from wild-type mice with late sepsis confirmed our findings in the S100A9 knockout mice. We also found that while both IL-6 and IL-10 can activate S100A9 expression in naive Gr1+CD11b+ cells, only IL-10 can induce S100A9 nuclear localization. These results support that IL-10 drives the molecular path that generates MDSCs and enhances immunosuppression during late sepsis, and inform that targeting this immune repressor path may improve sepsis survival in mice.
Bah, Isatou; Kumbhare, Ajinkya; Nguyen, Lam; McCall, Charles E.; and El Gazzar, Mohamed. 2018. IL-10 Induces an Immune Repressor Pathway in Sepsis by Promoting S100A9 Nuclear Localization and MDSCdsc Development. Cellular Immunology. Vol.332 32-38. https://doi.org/10.1016/j.cellimm.2018.07.003 PMID: 30025864 ISSN: 0008-8749