The myeloid-related protein S100A9 reprograms Gr1CD11b 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 Gr1CD11b 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 Gr1CD11b 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.

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Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1⁺CD11b⁺ MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.

Few estimates are available of the need for assistive devices (ADs) in African settings. This study aimed to estimate population-level need for glasses and hearing aids in The Gambia based on (1) clinical impairment assessment, and (2) self-reported AD awareness, and explore the relationship between the two methods. The Gambia 2019 National Eye Health Survey is a nationally representative population-based sample of 9188 adults aged 35+ years. Participants underwent standardised clinical vision assessments including the need for glasses (distance and near). Approximately 25% of the sample underwent clinical assessment of hearing and hearing aid need. Data were also collected on self-reported awareness, need and access barriers to vision and hearing ADs. Overall, 5.6% of the study population needed distance glasses (95% CI 5.0–6.3), 45.9% (95% CI 44.2–47.5) needed near glasses and 25.5% (95% CI 22.2–29.2) needed hearing aids. Coverage for each AD was very low (<4%). The agreement between self-report and clinical impairment assessment for AD need was poor. In conclusion, there is high prevalence and very low coverage for distance glasses, near glasses and hearing aids in The Gambia. Self-report measures alone will not provide an accurate estimate of AD need.

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