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

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

Redox Biol

Instituto Teófilo Hernando for Drug Discovery. Department of Pharmacology. School of Medicine. Universidad Autónoma Madrid. Madrid, Spain; Instituto de Investigación Sanitario (IIS-IP), Hospital Universitario de La Princesa, Madrid, Spain. Electronic address:

Published: January 2021

AI Article Synopsis

  • Heme oxygenase-1 (HO-1) is an enzyme with protective effects, but its increased expression in aging may lead to harmful iron deposits in the brain.
  • A study using aged mice found that microglial HO-1 expression rises under inflammation, causing oxidative stress and cognitive decline due to iron overload.
  • Treatment with an HO-1 inhibitor or an iron chelator improved inflammation and behavioral issues, suggesting that modulating HO-1 could help mitigate neurotoxicity in aging.

Article Abstract

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) 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 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680814PMC
http://dx.doi.org/10.1016/j.redox.2020.101789DOI Listing

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