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Therapeutic Neutralization of the NLRP1 Inflammasome Reduces the Innate Immune Response and Improves Histopathology after Traumatic Brain Injury
Open accessAbstract
Traumatic brain injury elicits acute inflammation that in turn exacerbates primary brain damage. A crucial part of innate immunity in the immune privileged central nervous system involves production of proinflammatory cytokines mediated by inflammasome signaling. Here, we show that the nucleotide-binding, leucine-rich repeat pyrin domain containing protein 1 (NLRP1) inflammasome consisting of NLRP1, caspase-1, caspase-11, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), the X-linked inhibitor of apoptosis protein, and pannexin 1 is expressed in neurons of the cerebral cortex. Moderate parasagittal fluid-percussion injury (FPI) induced processing of interleukin-1β, activation of caspase-1, cleavage of X-linked inhibitor of apoptosis protein, and promoted assembly of the NLRP1 inflammasome complex. Anti-ASC neutralizing antibodies administered immediately after fluid-percussion injury to injured rats reduced caspase-1 activation, X-linked inhibitor of apoptosis protein cleavage, and processing of interleukin-1β, resulting in a significant decrease in contusion volume. These studies show that the NLRP1 inflammasome constitutes an important component of the innate central nervous system inflammatory response after traumatic brain injury and may be a novel therapeutic target for reducing the damaging effects of posttraumatic brain inflammation.
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“several studies have characterized inflammasomes in neurons (de Rivero Vaccari et al, 2009;Kummer et al, 2007), which are capable of producing IL-1β (de Rivero Vaccari et al, 2009).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as de Rivero Vaccari et al, 2009
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Metadata
- Authors
- de Rivero Vaccari, J. P., Lotocki, G., Alonso, O. F., Bramlett, H. M., Dietrich, W. D., & Keane, R. W.
- Affiliations
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- University of Miami (US)
- Corresponding author
- Keane, Robert W
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2009-04-29
- Volume
- 29
- Issue
- 7
- Pages
- 1251-1261
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC2846547
- OpenAlex
- W2012789061
- Cited by
- 312
- References
- 43
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 15 · 2023: 16 · 2022: 27 · 2021: 17 · 2020: 32 · 2019: 17 · 2018: 24 · 2017: 21 · 2016: 18 · 2015: 26 · 2014: 27 · 2013: 20 · 2012: 14
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (NN42133)
- National Institute of Neurological Disorders and Stroke (NS-30291, R01NS042133, R01NS056072, P50NS030291)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- NLRP1 inflammasome, traumatic brain injury, innate immunity, caspase-1, caspase-11, interleukin-1β processing, XIAP, ASC, pannexin 1, fluid percussion injury, neuroinflammation, cortical neurons, contusion volume, therapeutic target
- MeSH terms
- Animals, Antibodies, Monoclonal, Epitopes, Brain Injuries, Immunity, Innate, Inflammation, Male, Nerve Tissue Proteins, Rats, Sprague-Dawley, Caspase 1, Multiprotein Complexes, Rats, Interleukin-1beta
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