Vimentin regulates activation of the NLRP3 inflammasome

Nat Commun. 2015 Mar 12;6:6574. doi: 10.1038/ncomms7574.

Abstract

Activation of the NLRP3 inflammasome and subsequent maturation of IL-1β have been implicated in acute lung injury (ALI), resulting in inflammation and fibrosis. We investigated the role of vimentin, a type III intermediate filament, in this process using three well-characterized murine models of ALI known to require NLRP3 inflammasome activation. We demonstrate that central pathophysiologic events in ALI (inflammation, IL-1β levels, endothelial and alveolar epithelial barrier permeability, remodelling and fibrosis) are attenuated in the lungs of Vim(-/-) mice challenged with LPS, bleomycin and asbestos. Bone marrow chimeric mice lacking vimentin have reduced IL-1β levels and attenuated lung injury and fibrosis following bleomycin exposure. Furthermore, decreased active caspase-1 and IL-1β levels are observed in vitro in Vim(-/-) and vimentin-knockdown macrophages. Importantly, we show direct protein-protein interaction between NLRP3 and vimentin. This study provides insights into lung inflammation and fibrosis and suggests that vimentin may be a key regulator of the NLRP3 inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Lung Injury / metabolism
  • Animals
  • Bleomycin / chemistry
  • Bone Marrow Cells / cytology
  • Bronchoalveolar Lavage Fluid
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Proliferation
  • Female
  • Fibrosis
  • Inflammasomes / metabolism*
  • Inflammation / metabolism*
  • Interleukin-1beta / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Atomic Force
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Interaction Mapping
  • Vimentin / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Vimentin
  • Bleomycin