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Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and
activation via SIRT3-mediated activation of superoxide dismutase 2
#MMPMID28584055
Traba J
; Geiger SS
; Kwarteng-Siaw M
; Han K
; Ra OH
; Siegel RM
; Gius D
; Sack MN
J Biol Chem
2017[Jul]; 292
(29
): 12153-12164
PMID28584055
show ga
Twenty-four hours of fasting is known to blunt activation of the human NLRP3
inflammasome. This effect might be mediated by SIRT3 activation, controlling
mitochondrial reactive oxygen species. To characterize the molecular
underpinnings of this fasting effect, we comparatively analyzed the NLRP3
inflammasome response to nutrient deprivation in wild-type and SIRT3 knock-out
mice. Consistent with previous findings for human NLRP3, prolonged fasting
blunted the inflammasome in wild-type mice but not in SIRT3 knock-out mice. In
SIRT3 knock-out bone marrow-derived macrophages, NLRP3 activation promoted excess
cytosolic extrusion of mitochondrial DNA along with increased reactive oxygen
species and reduced superoxide dismutase 2 (SOD2) activity. Interestingly, the
negative regulatory effect of SIRT3 on NLRP3 was not due to transcriptional
control or priming of canonical inflammasome components but, rather, occurred via
SIRT3-mediated deacetylation of mitochondrial SOD2, leading to SOD2 activation.
We also found that siRNA knockdown of SIRT3 or SOD2 increased NLRP3 supercomplex
formation and activation. Moreover, overexpression of wild-type and
constitutively active SOD2 similarly blunted inflammasome assembly and
activation, effects that were abrogated by acetylation mimic-modified SOD2.
Finally, in vivo administration of lipopolysaccharide increased liver injury and
the levels of peritoneal macrophage cytokines, including IL-1?, in SIRT3 KO mice.
These results support the emerging concept that enhancing mitochondrial
resilience against damage-associated molecular patterns may play a pivotal role
in preventing inflammation and that the anti-inflammatory effect of
fasting-mimetic diets may be mediated, in part, through SIRT3-directed blunting
of NLRP3 inflammasome assembly and activation.
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