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

doi:10.1038/ncomms7574

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

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

211 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 language	English (US)
Article number	6574
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7574
State	Published - Mar 12 2015

Funding

Dr Esra Roan (University of Memphis, TN) generously assisted with the AFM micro-indentation Matlab code and analysis of results. We thank Mr Luke Skertich for assistance with immunofluorescence confocal microscopy. Histological staining was performed by the Mouse Histology Phenotyping Laboratory. Imaging work was performed at the Northwestern University Cell Imaging Facility generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. AFM measurements were produced in the NIFTI facility (NUANCE Center, Northwestern University), which has received support from the NSF-NSEC, NSF-MRSEC, Keck Foundation, the State of Illinois and Northwestern University. Flow cytometry was supported by the Northwestern University Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553). This work was supported by National Heart, Lung, and Blood Institute (HL71643; HL124664), Department of Veterans Affairs (MERIT Award), Training Program in Lung Science (NIH-T32HL076139; M.R.R.), American Heart Association (AHA 10PRE4210064; M.R.R.) and National Heart, Lung and Blood Institute (NIH K08 HL093216; A.P.L.).

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms7574

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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, Article 6574. https://doi.org/10.1038/ncomms7574

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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.",

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

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AU - Morales-Nebreda, Luisa

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AU - Kutuzov, Mikhail A.

AU - Sitikov, Albert

AU - Davis, Jennifer M.

AU - Lam, Anna P.

AU - Cheresh, Paul

AU - Kamp, David

AU - Shumaker, Dale K.

AU - Budinger, G. R Scott

AU - Ridge, Karen M.

PY - 2015/3/12

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N2 - 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.

AB - 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.

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Vimentin regulates activation of the NLRP3 inflammasome

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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