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Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism

Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible...

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Autores principales: Fernández-Mendívil, Cristina, Luengo, Enrique, Trigo-Alonso, Paula, García-Magro, Nuria, Negredo, Pilar, López, Manuela G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680814/
https://www.ncbi.nlm.nih.gov/pubmed/33212416
http://dx.doi.org/10.1016/j.redox.2020.101789
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author Fernández-Mendívil, Cristina
Luengo, Enrique
Trigo-Alonso, Paula
García-Magro, Nuria
Negredo, Pilar
López, Manuela G.
author_facet Fernández-Mendívil, Cristina
Luengo, Enrique
Trigo-Alonso, Paula
García-Magro, Nuria
Negredo, Pilar
López, Manuela G.
author_sort Fernández-Mendívil, Cristina
collection PubMed
description Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1(△△) (HMOX1(M-KO)) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, TNF-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1(M-KO) and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult.
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spelling pubmed-76808142020-11-27 Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism Fernández-Mendívil, Cristina Luengo, Enrique Trigo-Alonso, Paula García-Magro, Nuria Negredo, Pilar López, Manuela G. Redox Biol Research Paper Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1(△△) (HMOX1(M-KO)) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, TNF-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1(M-KO) and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult. Elsevier 2020-11-06 /pmc/articles/PMC7680814/ /pubmed/33212416 http://dx.doi.org/10.1016/j.redox.2020.101789 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Fernández-Mendívil, Cristina
Luengo, Enrique
Trigo-Alonso, Paula
García-Magro, Nuria
Negredo, Pilar
López, Manuela G.
Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title_full Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title_fullStr Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title_full_unstemmed Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title_short Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism
title_sort protective role of microglial ho-1 blockade in aging: implication of iron metabolism
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680814/
https://www.ncbi.nlm.nih.gov/pubmed/33212416
http://dx.doi.org/10.1016/j.redox.2020.101789
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