J Cereb Blood Flow Metab. 2009 Mar;29(3):534-44. Epub 2008 Dec 10.

Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice.External

Abulafia, D. P., de Rivero Vaccari, J. P., Lozano, J. D., Lotocki, G., Keane, R. W., Dietrich, W. D.,
--- - Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Inflammation is a major contributor to the pathogenesis of cerebral ischemia and stroke. In the peripheral immune response, caspase-1 activation involves the formation of a macromolecular complex termed the inflammasome. We determined whether nucleotide-binding, leucine-rich repeat, pyrin domain containing 1 (NLRP1), molecular platform consisting of capase-1, apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC), and NLRP1, is expressed in the normal and postischemic brain. Mice underwent thromboembolic stroke to investigate the formation of the inflammasome and subsequent activation of downstream inflammatory responses. Western blot analysis showed expression and activation of interleukin (IL) IL-1beta and IL-18 at 24 h after stroke. Size-exclusion chromatography and coimmunoprecipitation analysis showed protein association between NLRP1, ASC, caspase-1, and the X-linked inhibitor of apoptosis protein (XIAP). After ischemia, immunohistochemical analysis revealed inflammasome proteins in neurons, astrocytes, and microglia/macrophages. The potential of the inflammasome as an antiinflammatory target was showed by interference of inflammasome activation resulting in reduced cytokine levels in mice treated after ischemia with a neutralizing antibody against NLRP1. These findings show that the inflammasome complex forms after focal brain ischemia and may be a novel therapeutic target for reducing the detrimental consequences of postischemic inflammation.
PMID: 19066616External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
CARD ASC Link Caspase1 Size-exclusion chromatography Mice cerebral cortex 19066616
CARD Caspase1 Link NLRP1 Size-exclusion chromatography Mice cerebral cortex 19066616
PYD ASC Link NLRP1 Size-exclusion chromatography Mice cerebral cortex 19066616
(Link: click this icon to show interactions only between the two corresponding DDs)