Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis

Abstract

Obesity increases morbidity and mortality in acute illnesses such as sepsis and septic shock. We showed previously that the early/hyper-inflammatory phase of sepsis is exaggerated in obese mice with sepsis; sirtuin 2 (SIRT2) modulates sepsis inflammation in obesity. Evidence suggests that obesity with sepsis is associated with increased oxidative stress. It is unknown whether exaggerated hyper-inflammation of obesity with sepsis modulates the SIRT2 function in return. We showed recently that SIRT6 oxidation during hyper-inflammation of sepsis modulates its glycolytic function. This study tested the hypothesis that increased oxidative stress and direct SIRT2 oxidation exaggerate hyper-inflammation in obesity with sepsis. Using spleen and liver tissue from mice with diet-induced obesity (DIO) we studied oxidized vs. total SIRT2 expression during hyper- and hypo-inflammation of sepsis. To elucidate the mechanism of SIRT2 oxidation (specific modifications of redox-sensitive cysteines) and its effect on inflammation, we performed site-directed mutations of redox-sensitive cysteines Cys221 and Cys224 on SIRT2 to serine (C221S and C224S), transfected HEK293 cells with mutants or WT SIRT2, and studied SIRT2 enzymatic activity and NFĸBp65 deacetylation. Finally, we studied the effect of SIRT2 mutation on LPS-induced inflammation using RAW 264.7 macrophages. In an inverse relationship, total SIRT2 decreased while oxidized SIRT2 expression increased during hyper-inflammation and SIRT2 was unable to deacetylate NFĸBp65 with increased oxidative stress of obesity with sepsis. Mechanistically, both the mutants (C221S and C224S) show decreased (1) SIRT2 enzymatic activity, (2) deacetylation of NFĸBp65, and (3) anti-inflammatory activity in response to LPS vs. WT SIRT2. Direct oxidation modulates SIRT2 function during hyper-inflammatory phase of obesity with sepsis via redox sensitive cysteines.

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Abbreviations

CLP :

Cecal ligation and puncture

CTRL :

Control diet mice

Cys :

Cysteine

DIO :

Diet induced obesity

LPS :

Lipopolysaccharide

NAD :

Nicotinamide dinucleotide

NFĸB :

Nuclear factor kappa B

Ob/ob :

B6.Cg-Lepob/J

PM :

Peritoneal macrophages

SIRT :

Sirtuin

SIRT1 :

Sirtuin 1

SIRT2 :

Sirtuin 2

TBH :

Tertiary-butyl hydroperoxide

WT :

Wild type (lean)

BP1 :

Biotin-1,3-cyclopentanedione

NEM :

N-ethyl maleimide

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Acknowledgements

The plasmids were gifted to us by Addgene; pcDNA3β-FLAG-CBP-HA was a gift from Tso-Pang Yao (Addgene plasmid #32908); pCMV4 NFĸB p65 was a gift from Warner Greene (Addgene plasmid #21966). Wild-type plasmid SIRT2 flag was a gift from Eric Verdin (Addgene plasmid #13813).

Funding

This work was supported by NIH grants: Vidula T. Vachharajani, R01GM099807; Charles E McCall, (1) R01AI065791, (2) R01AI079144 (3) 1R35GM126922.

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Contributions

Concept and design: VTV and CF; data collection: XW, NB, DL and VTV; data analysis and interpretation: VTV, XW, CEM and CF; generating the manuscript: VTV, XW, CEM and CF.

Corresponding author

Correspondence to Vidula Vachharajani.

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The authors declare that the submitted work was not carried out in the presence of any personal, professional or financial relationships that could potentially be construed as a conflict of interest.

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Summary statement: Cysteine thiols regulate SIRT2 during hyper-inflammation of obesity with sepsis

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Wang, X., Buechler, N.L., Long, D.L. et al. Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis. Inflammation 42, 156–169 (2019). https://doi.org/10.1007/s10753-018-0881-9

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KEY WORDS

  • obesity
  • sepsis
  • septic shock
  • hyper-inflammation
  • oxidative stress