The Journal of Immunology, 2007, 178: B70.
Copyright © 2007 by The American Association of Immunologists, Inc.
Thromboembolic stroke promotes the formation of the inflammasome complex
Denise P Abulafia1,
J Pablo de Rivero Vaccari2,
J Diego Lozano3,
Timothy J Ragan4,
Robert W Keane2 and
W Dalton Dietrich3
1 Department of Cell Biology and Anatomy,
2 Department of Physiology and Biophysics,
3 The Miami Project to Cure Paralysis,
4 Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, 1095 NW14th Terrace, LPLC R-48 Room 3-25, Miami, Florida, 33136
Abstract
Inflammatory responses contribute to the pathogenesis of cerebral ischemia and stroke. Activated caspase-1 cleaves the pro-inflammatory cytokines IL-1
and IL-18, initiating a cascade of detrimental inflammatory events. Cell culture studies of macrophages have reported that activation of caspase-1 involves the formation of a macromolecular complex termed the inflammasome. Whether this complex is present after cerebral ischemia is unknown. Here, we utilized a clinically relevant model of thromboembolic stroke in mice to investigate the formation of the inflammasome and subsequent activation of inflammatory responses. Our results demonstrate for the first time that cerebral ischemia triggered the formation of a high molecular weight complex comprised of caspase-1, caspase-11, the adaptor protein ASC (apoptosis-associated speck-like protein with CARD) and NALP1 (NACHT/LRR/pyrin domain-containing protein 1) in the cerebral cortex, 24 hr after ischemia. Formation of the inflammasome complex resulted in activation of caspase-1 and cleavage of IL-1 and IL-18. Immunohistochemical analysis revealed the presence of inflammasome proteins in cortical neurons and inflammatory cells. Finally, the therapeutic potential of targeting the inflammasome after ischemia was demonstrated by reduced cytokine activation in mice treated with a neutralizing antibody against NALP1.
