Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice.
OBJECTIVE:Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that s...
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doaj-8e294c943f174df684a956a65e2c53c42020-11-24T21:08:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01118e016043110.1371/journal.pone.0160431Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice.Xianfeng WangNancy L BuechlerAyana MartinJonathan WellsBarbara YozaCharles E McCallVidula VachharajaniOBJECTIVE:Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. METHODS:Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. RESULTS:We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. CONCLUSION:SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.http://europepmc.org/articles/PMC4976857?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xianfeng Wang Nancy L Buechler Ayana Martin Jonathan Wells Barbara Yoza Charles E McCall Vidula Vachharajani |
spellingShingle |
Xianfeng Wang Nancy L Buechler Ayana Martin Jonathan Wells Barbara Yoza Charles E McCall Vidula Vachharajani Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. PLoS ONE |
author_facet |
Xianfeng Wang Nancy L Buechler Ayana Martin Jonathan Wells Barbara Yoza Charles E McCall Vidula Vachharajani |
author_sort |
Xianfeng Wang |
title |
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. |
title_short |
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. |
title_full |
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. |
title_fullStr |
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. |
title_full_unstemmed |
Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. |
title_sort |
sirtuin-2 regulates sepsis inflammation in ob/ob mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2016-01-01 |
description |
OBJECTIVE:Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. METHODS:Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. RESULTS:We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65. CONCLUSION:SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis. |
url |
http://europepmc.org/articles/PMC4976857?pdf=render |
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