Interferon-β alleviates sepsis by SIRT1-mediated blockage of endothelial glycocalyx shedding
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Sepsis is a life-threatening multi-organ dysfunction with highmortality caused by the body’s improper response to microbialinfection. No new effective therapy has emerged that can adequatelytreat patients with sepsis. We previously demonstratedthat interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reportedits significant protective effect against acute respiratorydistress syndrome, a complication of severe sepsis, in humanpatients. However, the IFN-β effect cannot solely be explainedby SIRT1-mediated immunosuppression, since sepsis inducesimmunosuppression in patients. Here, we show that IFN-β, incombination with nicotinamide riboside (NR), alleviates sepsisby blocking endothelial damage via SIRT1 activation. IFN-βplus NR protected against cecal ligation puncture-(CLP)-inducedsepsis in wild-type mice, but not in endothelial cell-specificSirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1protein expression in endothelial cells in a protein synthesisindependentmanner. IFN-β plus NR reduced the CLP-inducedincrease in in vivo endothelial permeability in wild-type, butnot EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effectwas abolished by Sirt1 knockdown in endothelial cells. Ourresults suggest that IFN-β plus NR protects against endothelialdamage during sepsis via activation of the SIRT1/heparinase 1pathway.
Abstract
Sepsis is a life-threatening multi-organ dysfunction with highmortality caused by the body’s improper response to microbialinfection. No new effective therapy has emerged that can adequatelytreat patients with sepsis. We previously demonstratedthat interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reportedits significant protective effect against acute respiratorydistress syndrome, a complication of severe sepsis, in humanpatients. However, the IFN-β effect cannot solely be explainedby SIRT1-mediated immunosuppression, since sepsis inducesimmunosuppression in patients. Here, we show that IFN-β, incombination with nicotinamide riboside (NR), alleviates sepsisby blocking endothelial damage via SIRT1 activation. IFN-βplus NR protected against cecal ligation puncture-(CLP)-inducedsepsis in wild-type mice, but not in endothelial cell-specificSirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1protein expression in endothelial cells in a protein synthesisindependentmanner. IFN-β plus NR reduced the CLP-inducedincrease in in vivo endothelial permeability in wild-type, butnot EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effectwas abolished by Sirt1 knockdown in endothelial cells. Ourresults suggest that IFN-β plus NR protects against endothelialdamage during sepsis via activation of the SIRT1/heparinase 1pathway.
참고문헌 (21)
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