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

Denise P. Abulafia, Juan Pablo De Rivero Vaccari, J. Diego Lozano, George Lotocki, Robert W. Keane, W. Dalton Dietrich

Research output: Contribution to journalArticle

194 Scopus citations

Abstract

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-1β 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.

Original languageEnglish (US)
Pages (from-to)534-544
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume29
Issue number3
DOIs
StatePublished - Jan 1 2009

Keywords

  • Focal ischemia
  • Inflammasome
  • Inflammation
  • Interleukins
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

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