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Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):4050-5. doi: 10.1073/pnas.1419090112. Epub 2015 Mar 16.

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3.

Author information

1
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, 1083, Hungary; Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and david.brough@manchester.ac.uk denesa@koki.hu.
2
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and.
3
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, 1083, Hungary;
4
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and Inflammation and Experimental Surgery Unit, CIBERehd (Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas), Murcia Biohealth Research Institute-Arrixaca, University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
5
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and david.brough@manchester.ac.uk denesa@koki.hu.

Abstract

Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.

KEYWORDS:

brain injury; cell death; cerebral ischemia; inflammasome; inflammation

PMID:
25775556
PMCID:
PMC4386342
DOI:
10.1073/pnas.1419090112
[Indexed for MEDLINE]
Free PMC Article

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