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Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology
Subarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated wi...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Limited
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484865/ https://www.ncbi.nlm.nih.gov/pubmed/22679224 http://dx.doi.org/10.1242/dmm.008557 |
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author | Greenhalgh, Andrew D. Brough, David Robinson, Emily M. Girard, Sylvie Rothwell, Nancy J. Allan, Stuart M. |
author_facet | Greenhalgh, Andrew D. Brough, David Robinson, Emily M. Girard, Sylvie Rothwell, Nancy J. Allan, Stuart M. |
author_sort | Greenhalgh, Andrew D. |
collection | PubMed |
description | Subarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra) reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1) was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC). Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs) in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP) driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease. |
format | Online Article Text |
id | pubmed-3484865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Company of Biologists Limited |
record_format | MEDLINE/PubMed |
spelling | pubmed-34848652012-11-16 Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology Greenhalgh, Andrew D. Brough, David Robinson, Emily M. Girard, Sylvie Rothwell, Nancy J. Allan, Stuart M. Dis Model Mech Research Article Subarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra) reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1) was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC). Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs) in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP) driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease. The Company of Biologists Limited 2012-11 2012-05-31 /pmc/articles/PMC3484865/ /pubmed/22679224 http://dx.doi.org/10.1242/dmm.008557 Text en © 2012. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms. |
spellingShingle | Research Article Greenhalgh, Andrew D. Brough, David Robinson, Emily M. Girard, Sylvie Rothwell, Nancy J. Allan, Stuart M. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title | Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title_full | Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title_fullStr | Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title_full_unstemmed | Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title_short | Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
title_sort | interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484865/ https://www.ncbi.nlm.nih.gov/pubmed/22679224 http://dx.doi.org/10.1242/dmm.008557 |
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