Modulation of TNF ‐α mRNA stability by human antigen R and miR181s in sepsis‐induced immunoparalysis

Abstract

Immunoparalysis is an important pathological mechanism in sepsis. However, an effective small molecule therapy is lacking. Here, we show that ouabain, a Na + ,K + ‐ ATP ase ligand, can reverse immunoparalysis in vitro , in vivo , and in clinical samples. Notably, the effect of ouabain was critically dependent on TNF ‐α expression. However, ouabain had opposing effects on the stability of TNF ‐α mRNA : Ouabain triggered miR‐181 transcription, which promoted TNF ‐α mRNA degradation and induced immunoparalysis, and ouabain triggered the nuclear export of human antigen R (HuR), which stabilized TNF ‐α mRNA and suppressed immuno‐paralysis. Interestingly, because the miR‐181 binding site is located within the HuR binding site in the 3′‐untranslated region of TNF ‐α, in ouabain‐treated cells, HuR competed with miR‐181 for binding to TNF ‐α mRNA and recruited TNF ‐α mRNA to stress granules, thereby stabilizing TNF ‐α mRNA and reversing immunoparalysis. Ouabain also induced GM ‐ CSF and interferon‐γ expression in a HuR‐dependent manner. Hence, the fine‐tuning of TNF ‐α mRNA stability by HuR and miR181 plays a crucial role in immunoparalysis, and Na + ,K + ‐ ATP ase ligands are promising agents for immunoparalysis therapy. image Ouabain, a Na + ,K + ‐ ATP ase ligand, is shown as the first small molecule able to reverse sepsis‐induced immunoparalysis in rodents and in clinical samples through a novel mechanism resulting in TH 1 cytokines post‐transcriptional reprogramming in monocytes. Sepsis‐induced immunoparalysis can be improved by reprogramming TH 1 cytokines expression at post‐transcriptional level. Modulation of TNF ‐α expression in monocytes is critically involved in sepsis‐induced endotoxin tolerance and immunoparalysis. TNF ‐α mRNA stability is finely regulated by HuR and miR181s. Sepsis‐induced immunoparalysis can be reversed by the small molecule drug ouabain. TH 1 cytokines expression can be post‐transcriptionally modulated by cardiac glycosides.