Vimentin regulates activation of the NLRP3 inflammasome

Our plain-English summary of Vimentin regulates activation of the NLRP3 inflammasome, by G. dos Santos, M.R. Rogel, M.A. Baker, et al (Nature Communications, 2015).

The study

• Authors: G. dos Santos, M.R. Rogel, M.A. Baker, J.R. Troken, D. Urich, L. Morales-Nebreda, J.A. Sennello, M.A. Kutuzov, A. Sitikov, J.M. Davis, A.P. Lam, P. Cheresh, D. Kamp, D.K. Shumaker, G.R. Budinger, K.M. Ridge
• Journal: Nature Communications
• Published: 2015;6:6574
• Cited by: 246 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice and in cultured mouse and human cells, not people. The authors tested whether vimentin, a structural cell protein, is needed to activate the NLRP3 inflammasome, a protein complex that leads caspase-1 to convert pro-IL-1β into active IL-1β. Normal mice and mice lacking vimentin received LPS (a bacterial product) by abdominal injection, or bleomycin (a drug) or crocidolite asbestos into the airway. Titanium dioxide was an inert comparison particle. After asbestos, mice lacking vimentin had significantly fewer cells recruited to the lungs. They lacked the lung-fluid protein rise seen in normal mice and had lower caspase-1 and IL-1β. Normal mice developed pulmonary fibrosis; mice lacking vimentin showed no significant collagen increase. After LPS, mice lacking vimentin had less lung injury and less caspase-1 and IL-1β, but similar inflammatory-cell recruitment; after bleomycin, they had less injury and fibrosis. Human macrophage-like cells with reduced vimentin also showed repressed inflammasome activation with asbestos. The authors reported that vimentin binds directly to NLRP3. They concluded that vimentin may be a key regulator of the NLRP3 inflammasome.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiments using vimentin knockout and wild-type mice in three lung-injury models (LPS, bleomycin, asbestos), plus bone marrow chimeric mice and laboratory cell experiments
• Who was studied: Age- and sex-matched 8- to 10-week-old wild-type and vimentin-deficient (Vim−/−) mice, bred at Northwestern University. In the asbestos experiments there were 6 to 8 animals per group across two independent experiments. The study also used mouse macrophages (alveolar, bone marrow-derived, J774 cell line) and the human THP-1 macrophage-like cell line.
• Exposure: Crocidolite asbestos given intratracheally (dose printed as '200 mg', units apparently damaged in the text), compared with the inert particle titanium dioxide (TiO2). Bleomycin was also given intratracheally. LPS was given by intraperitoneal injection. In cell experiments, THP-1 cells were also exposed to asbestos and to monosodium urate (MSU).
• Main results:
  • After asbestos exposure, significantly fewer cells were recruited to the lungs of vimentin-deficient mice than of wild-type mice.
  • After asbestos, wild-type mice showed increased total protein in lung lavage fluid; vimentin-deficient mice did not.
  • Asbestos-exposed vimentin-deficient mice had reduced caspase-1 and IL-1β in lung lavage fluid compared with wild-type mice.
  • Wild-type mice exposed to asbestos developed pulmonary fibrosis. In vimentin-deficient mice, no significant increase in collagen deposition was seen.
  • After LPS, wild-type mice had significantly more caspase-1 and mature IL-1β in lung lavage fluid than vimentin-deficient mice.
  • After LPS, the authors found that protection in vimentin-deficient mice was not associated with impaired recruitment of inflammatory cells to the lung.
  • After 5 days of bleomycin, lung inflammation, wet-to-dry lung weight ratio and lavage protein were significantly attenuated in vimentin-deficient mice compared with wild-type mice.
  • In human macrophage-like cells with vimentin knocked down, inflammasome activation (IL-1β and caspase-1 in cell supernatants) was repressed with MSU, and similar results were obtained with asbestos.
  • Lung collagen 21 days after bleomycin was 0.57 ± 0.09 mg per lung in wild-type mice and 0.31 ± 0.03 mg per lung in vimentin-deficient mice.
  • After a lethal LPS dose, median survival was 138 h in vimentin-deficient mice. In wild-type mice it was printed as 'B40 h', apparently about 40 h.
  • In bone marrow chimeric mice given bleomycin, the increases in IL-1β, IL-6 and TGF-β seen in mice with wild-type marrow were significantly attenuated in mice with vimentin-deficient marrow.
  • Bio-layer interferometry showed NLRP3 binding to vimentin, with a dissociation constant of 640 nM.
• The authors' conclusion: The authors concluded that vimentin may be a key regulator of the NLRP3 inflammasome.
• Limitations the authors state:
  • The authors attributed the incomplete suppression of IL-1β in the chimeric mice to incomplete chimerism, with only about 90% engraftment.
  • The authors stated that how vimentin mediates inflammasome activation is unresolved.
  • The authors stated they can only speculate about where and how vimentin associates with NLRP3 and caspase-1.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Fibrosis, Macrophage.

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