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Defective mitochondrial fission augments NLRP3 inflammasome activation

 Sangjun Park  ;  Ji-Hee Won  ;  Inhwa Hwang  ;  Sujeong Hong  ;  Heung Kyu Lee  ;  Je-Wook Yu 
 SCIENTIFIC REPORTS, Vol.5 : 15489, 2015 
Journal Title
Issue Date
Animals ; Carrier Proteins/biosynthesis* ; Carrier Proteins/genetics ; Caspase 1/genetics ; Dynamins/biosynthesis* ; Dynamins/genetics ; Gene Expression Regulation ; Inflammasomes/biosynthesis ; Inflammasomes/genetics* ; Inflammation/genetics* ; Inflammation/pathology ; Interleukin-1beta/genetics ; MAP Kinase Signaling System/genetics ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Mitochondria/genetics ; Mitochondria/pathology ; Mitochondrial Dynamics/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/metabolism
Despite the fact that deregulated NLRP3 inflammasome activation contributes to the pathogenesis of chronic inflammatory or metabolic disorders, the underlying mechanism by which NLRP3 inflammasome signaling is initiated or potentiated remains poorly understood. Much attention is being paid to mitochondria as a regulator of NLRP3 inflammasome activation, but little is known about the role of mitochondrial dynamics for the inflammasome pathway. Here, we present evidence that aberrant mitochondrial elongation caused by the knockdown of dynamin-related protein 1 (Drp1) lead to a marked increase in NLRP3-dependent caspase-1 activation and interleukin-1-beta secretion in mouse bone marrow-derived macrophages. Conversely, carbonyl cyanide m-chlorophenyl hydrazone, a chemical inducer of mitochondrial fission, clearly attenuated NLRP3 inflammasome assembly and activation. Augmented activation of NLRP3 inflammasome by mitochondrial elongation is not resulted from the increased mitochondrial damages of Drp1-knockdown cells. Notably, enhanced extracellular signal-regulated kinase (ERK) signaling in Drp1-knockdown macrophages is implicated in the potentiation of NLRP3 inflammasome activation, possibly via mediating mitochondrial localization of NLRP3 to facilitate the assembly of NLRP3 inflammasome. Taken together, our results provide a molecular insight into the importance of mitochondrial dynamics in potentiating NLRP3 inflammasome activation, leading to aberrant inflammation.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
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