title: NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice.
abstract: Acute inflammation in response to both exogenous and endogenous danger signals can lead to the assembly of cytoplasmic inflammasomes that stimulate the activation of caspase-1. Subsequently, caspase-1 facilitates the maturation and release of cytokines and also, under some circumstances, the induction of cell death by pyroptosis. Using a mouse line lacking expression of NLRP1, we show that assembly of this inflammasome in cells is triggered by a toxin from anthrax and that it initiates caspase-1 activation and release of IL-1β. Furthermore, NLRP1 inflammasome activation also leads to cell death, which escalates over 3 d following exposure to the toxin and culminates in acute lung injury and death of the mice. We show that these events are not dependent on production of IL-1β by the inflammasome but are dependent on caspase-1 expression. In contrast, muramyl dipeptide-mediated inflammasome formation is not dependent on NLRP1 but NLRP3. Taken together, our findings show that assembly of the NLRP1 inflammasome is sufficient to initiate pyroptosis, which subsequently leads to a self-amplifying cascade of cell injury within the lung from which the lung cannot recover, eventually resulting in catastrophic consequences for the organism.
authors: Pulmonary Division, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Martina
authors: M
authors: Kovarova
authors: Pamela R
authors: PR
authors: Hesker
authors: Leigh
authors: L
authors: Jania
authors: MyTrang
authors: M
authors: Nguyen
authors: John N
authors: JN
authors: Snouwaert
authors: Zhidan
authors: Z
authors: Xiang
authors: Stephen E
authors: SE
authors: Lommatzsch
authors: Max T
authors: MT
authors: Huang
authors: Jenny P-Y
authors: JP
authors: Ting
authors: Beverly H
authors: BH
authors: Koller
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D005434:Flow Cytometry; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; C529636:NALP1 protein, mouse; D020170:Caspase 1