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, remodeling, 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 vimentin may be a key regulator of the NLRP3 inflammasome.

The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

“…In contrast to observations in cancer, our data support a reciprocal regulatory process, in which vimentin network integrity is important for downstream mTORC2 signaling. This role for vimentin is similar to the one that it plays in NLRP3 and NOD/NLRP1 inflammasome signaling in immune cells, in which vimentin's scaffold function is a critical upstream component of these cascades (48,49). Additionally, our data suggest that vimentin-mediated support of PKC-θ may in turn bolster mTORC2 function through the intermediary molecule IKK (27,50).…”

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro

“…Bleomycin (BLE) is a drug for the treatment of a variety of human malignancies [13]. Administration of BLE has been used to study the pathogenesis and intervention of ALI in mice [14].…”

Influenza A Virus Infection, Innate Immunity, and Childhood

“…The NLRP3 inflammasome assembly has recently been shown to require the intermediate filament vimentin, which may act as a scaffold on which inflammasome components can converge. 28 Two signals are required for inflammasome activation, including a priming signal that induces production of the precursor cytokines pro–IL-1β and pro– IL-18 via the transcription factor NF-κB and a second signal that leads to inflammasome assembly and cleavage of these precursors to their mature forms. In the case of IAV infection, the first signal is thought to occur through TLR3 or TLR7 recognition of the virus, leading to NF-κB activation and production of pro–IL-1β and pro–IL-18.…”