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

Autor: Nuria García-Magro, Cristina Fernández-Mendívil, Enrique Luengo, Paula Trigo-Alonso, Pilar Negredo, Manuela G. López
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
IL-1β
interleukin 1 beta
Lipopolysaccharides
Aging
NOR
novel object recognition test
Clinical Biochemistry
Anti-Inflammatory Agents
HO-1
heme oxygenase 1
NLRP3
pyrin domain containing 3
medicine.disease_cause
MCV
mean corpuscular volume
Biochemistry
PD
Parkinson's disease
DHE
dihydroethydium
Fn
ferritin
Mice
0302 clinical medicine
Neuroinflammation
TFR1
transferrin receptor 1
TNF-α
tumor necrosis factor alpha
Cognitive decline
lcsh:QH301-705.5
ANOVA
analysis of variance
EAE
experimental autoimmune encephalomyelitis
lcsh:R5-920
Microglia
Chemistry
NDD
neurodegenerative diseases
Iron metabolism
Deferoxamine
NRF2
nuclear factor (erythroid-derived 2)-like 2
medicine.anatomical_structure
CD163
cluster of differentiation 163
DFX
deferoxamine
OS
oxidative stress
CO
carbon monoxide
Heme oxygenase-1
GPX4
glutathione peroxidase 4
iNOS
inducible nitric oxide synthase
LPS
lipopolysaccharide
AD
Alzheimer's disease
lcsh:Medicine (General)
FPN1
ferroportin 1
ZnPP
zinc protoporphyrin
medicine.drug
Research Paper
medicine.medical_specialty
Iron
CNS
central nervous system
Neuroprotection
WBC
white cell counts
PI
propidium iodide
03 medical and health sciences
DMT1
divalent metal transporter 1
H2DCFDA
2′
7′-dichlorodihydrofluorescein diacetate
HCT
hematocrit
Internal medicine
medicine
Animals
Ferroptosis
NO
nitric oxide
Innate immune system
NFT
neurofibrillary tangles
Organic Chemistry
Wild type
Membrane Proteins
030104 developmental biology
Endocrinology
lcsh:Biology (General)
030217 neurology & neurosurgery
Oxidative stress
Hb
hemoglobin
Zdroj: Redox Biology, Vol 38, Iss, Pp 101789-(2021)
Redox Biology
ISSN: 2213-2317
Popis: 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△△ (HMOX1M-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 HMOX1M-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.
Graphical abstract Image 1
Highlights • Microglial HO-1 increases with aging and under an acute inflammatory stimulus. • LPS-dependent microglial HO-1 upregulation during aging leads to iron overload. • Microglial HO-1-dependent iron accumulation leads to ferroptosis. • HO-1-dependent iron alterations lead to neuroinflammation. • HO-1 inhibitors/iron chelators reduce iron accumulation and neuroinflammation.
Databáze: OpenAIRE
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