RT Journal Article
SR Electronic
T1 NLRP1-Dependent Pyroptosis Leads to Acute Lung Injury and Morbidity in Mice
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 2006
OP 2016
DO 10.4049/jimmunol.1201065
VO 189
IS 4
A1 Kovarova, Martina
A1 Hesker, Pamela R.
A1 Jania, Leigh
A1 Nguyen, MyTrang
A1 Snouwaert, John N.
A1 Xiang, Zhidan
A1 Lommatzsch, Stephen E.
A1 Huang, Max T.
A1 Ting, Jenny P.-Y.
A1 Koller, Beverly H.
YR 2012
UL http://www.jimmunol.org/content/189/4/2006.abstract
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.