Vimentin regulates activation of the NLRP3 inflammasome

Gimena Dos Santos, Micah R. Rogel, Margaret A. Baker, James R. Troken, Daniela Urich, Luisa Morales-Nebreda, Joseph A. Sennello, Mikhail A. Kutuzov, Albert Sitikov, Jennifer M. Davis, Anna P. Lam, Paul Cheresh, David Kamp, Dale K. Shumaker, G. R Scott Budinger, Karen M. Ridge*

*Corresponding author for this work

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88 Scopus citations

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.

Original languageEnglish (US)
Article number6574
JournalNature communications
Volume6
DOIs
StatePublished - Mar 12 2015

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Dos Santos, G., Rogel, M. R., Baker, M. A., Troken, J. R., Urich, D., Morales-Nebreda, L., Sennello, J. A., Kutuzov, M. A., Sitikov, A., Davis, J. M., Lam, A. P., Cheresh, P., Kamp, D., Shumaker, D. K., Budinger, G. R. S., & Ridge, K. M. (2015). Vimentin regulates activation of the NLRP3 inflammasome. Nature communications, 6, [6574]. https://doi.org/10.1038/ncomms7574