title: Vimentin regulates activation of the NLRP3 inflammasome.
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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Gimena
authors.identifier: 0000000293371833
authors.initials: G
authors.lastname: dos Santos
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Department of Biomedical Engineering, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Micah R
authors.initials: MR
authors.lastname: Rogel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Baker
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Troken
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sennello
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kutuzov
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Sitikov
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lam
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Veterans Administration, Chicago, Illinois 60612, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Veterans Administration, Chicago, Illinois 60612, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kamp
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Dale K
authors.initials: DK
authors.lastname: Shumaker
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Veterans Administration, Chicago, Illinois 60612, USA [3] Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: 1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Veterans Administration, Chicago, Illinois 60612, USA [3] Department of Cell and Molecular Biology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ridge
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D001992:Bronchoalveolar Lavage Fluid; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005355:Fibrosis; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018625:Microscopy, Atomic Force; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D025941:Protein Interaction Mapping; D014746:Vimentin / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014746:Vimentin; D001761:Bleomycin