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Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansi...

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Autores principales: Loan, James J. M., Al-Shahi Salman, Rustam, McColl, Barry W., Hardingham, Giles E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599325/
https://www.ncbi.nlm.nih.gov/pubmed/36291647
http://dx.doi.org/10.3390/biom12101438
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author Loan, James J. M.
Al-Shahi Salman, Rustam
McColl, Barry W.
Hardingham, Giles E.
author_facet Loan, James J. M.
Al-Shahi Salman, Rustam
McColl, Barry W.
Hardingham, Giles E.
author_sort Loan, James J. M.
collection PubMed
description Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH.
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spelling pubmed-95993252022-10-27 Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage Loan, James J. M. Al-Shahi Salman, Rustam McColl, Barry W. Hardingham, Giles E. Biomolecules Review Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH. MDPI 2022-10-07 /pmc/articles/PMC9599325/ /pubmed/36291647 http://dx.doi.org/10.3390/biom12101438 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Loan, James J. M.
Al-Shahi Salman, Rustam
McColl, Barry W.
Hardingham, Giles E.
Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title_full Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title_fullStr Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title_full_unstemmed Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title_short Activation of Nrf2 to Optimise Immune Responses to Intracerebral Haemorrhage
title_sort activation of nrf2 to optimise immune responses to intracerebral haemorrhage
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599325/
https://www.ncbi.nlm.nih.gov/pubmed/36291647
http://dx.doi.org/10.3390/biom12101438
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