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Inhibition of MicroRNA-23b Attenuates Immunosuppression During Late Sepsis Through NIK, TRAF1, and XIAP.

ABSTRACT: Background:microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis-induced immunosuppression. Methods:Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were investigated, and survival was monitored. T-cell immunoreactivities were examined during late sepsis. Nuclear factor κB (NF-κB)-inducing kinase (NIK), tumor necrosis factor (TNF)-receptor associated factor 1 (TRAF1), and X-linked inhibitor of apoptosis protein (XIAP), the putative targets of miR-23b, were identified by a dual-luciferase reporter assay. Results:miR-23b expression is upregulated and sustained during sepsis. The activation of the TLR4/TLR9/p38 MAPK/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased the number of spleen cells positive by terminal deoxynucleotidyl transferase dUTP nick-end labeling and improved survival. miR-23b inhibitor restored the immunoreactivity by alleviating the development of T-cell exhaustion and producing smaller amounts of immunosuppressive interleukin 10 and interleukin 4 during late sepsis. We demonstrated that miR-23b mediated immunosuppression during late sepsis by inhibiting the noncanonical NF-κB signal and promoting the proapoptotic signal pathway by targeting NIK, TRAF1, and XIAP. Conclusions:Inhibition of miR-23b reduces late-sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6009583 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis.MethodsSepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor-interacting protein kinase 1 inhibitor necrostatin-1 (10 µg/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses.ResultsAt 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4-, and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein-2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin-1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P = .11).ConclusionInhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis.

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Inhibition of MicroRNA-23b Attenuates Immunosuppression During Late Sepsis Through NIK, TRAF1, and XIAP.

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