PT  - JOURNAL ARTICLE
AU  - Kovarova, Martina
AU  - Hesker, Pamela R.
AU  - Jania, Leigh
AU  - Nguyen, MyTrang
AU  - Snouwaert, John N.
AU  - Xiang, Zhidan
AU  - Lommatzsch, Stephen E.
AU  - Huang, Max T.
AU  - Ting, Jenny P.-Y.
AU  - Koller, Beverly H.
TI  - NLRP1-Dependent Pyroptosis Leads to Acute Lung Injury and Morbidity in Mice
AID  - 10.4049/jimmunol.1201065
DP  - 2012 Aug 15
TA  - The Journal of Immunology
PG  - 2006--2016
VI  - 189
IP  - 4
4099  - http://www.jimmunol.org/content/189/4/2006.short
4100  - http://www.jimmunol.org/content/189/4/2006.full
SO  - J. Immunol.2012 Aug 15; 189
AB  - 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.