Defective mitochondrial fission augments NLRP3 inflammasome activation

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2015-10
Language
English
Article Type
Article
Keywords

DYNAMIN-RELATED PROTEIN-1; DEATH PATHWAYS; MITOFUSIN 2; CELL-DEATH; DISEASE; PROMOTES; AIM2; DRP1; ASC; PYROPTOSOME

Citation

SCIENTIFIC REPORTS, v.5

ISSN
2045-2322
DOI
10.1038/srep15489
URI
http://hdl.handle.net/10203/203670
Appears in Collection
MSE-Journal Papers(저널논문)
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