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.

doi:10.1016/j.redox.2020.101789

Cited by 112 publications

(87 citation statements)

References 79 publications

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“…The catalyzed metabolite ferrous iron is an essential element for neuronal functions, while iron overload has been known to cause neuronal toxicity through ER stress [43]. Besides, deletion of Hmox1 in microglia blocks iron overload-induced neuronal toxicity [34]. Excess HMOX1 may hence lead to ER stress via iron overload, which in turn may trigger the unfolded protein response (UPR) with the concomitant upregulation of PERK (protein kinase RNAlike ER kinase), ATF4 and ATF6 (activating transcription factor 4 and 6) and IRE1 (inositol-requiring enzyme 1) [22,44].…”

Section: Discussionmentioning

confidence: 99%

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High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

Liu

Lian

et al. 2021

Mol Neurodegeneration

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Background Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role. Methods Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of Müller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript 3 (Ddit3), is analyzed in a line of knockout mice. Results Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly induces photoreceptor degeneration even without light stress. Photoreceptor degeneration following high level expression of HMOX1 is associated with a mislocalization of rhodopsin in photoreceptors and an increase in the expression of DDIT3. Genetic deletion of Ddit3 in knockout mice prevents photoreceptor cell degeneration normally resulting from high level HMOX1 expression. Conclusion The results reveal that the expression levels determine whether HMOX1 is protective or deleterious in the retina. Furthermore, in contrast to the protective low dose of HMOX1, the deleterious high dose is associated with induction of DDIT3 and endoplasmic reticulum stress as manifested, for instance, in rhodopsin mislocalization. Hence, future applications of HMOX1 or its regulated targets in gene therapy approaches should carefully consider expression levels in order to avoid potentially devastating effects.

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Section: Discussionmentioning

confidence: 99%

“…Examination of iron levels was performed as previously reported, with small modifications [ 34 ]. Briefly, neural retinas were dissected in PBS, and each whole neural retina was incubated with 50 μl of 10% trichloroacetic acid (Sigma) and 3 M hydrochloric acid and subjected to shaking for 20 h at 1200 rpm at 65 °C.…”

Section: Methodsmentioning

confidence: 99%

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

Liu

Lian

et al. 2021

Mol Neurodegeneration

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“…It is not the case that everything associated with iron metabolism is necessarily deleterious in impact; Transferrin (Tf) has been suggested to increase microglial phagocytosis in the presence of a demyelinating lesion [ 139 ], as well as reducing nitrite release in response to lipopolysaccharide (LPS) stimulation. The accumulation of iron may be linked to overexpression of Heme-Oxygenase 1 (HMOX1) in aged microglia, suggesting yet another potential marker requiring further investigation [ 140 ]. The expression of HMOX1 in microglia has previously been suggested as a potential mechanism for preventing inflammation in the brain [ 141 ], possibly as a result of cooperation with astrocytes and diminished expression of IFN-γ.…”

Section: Microglia and Senescencementioning

confidence: 99%

Senescent Microglia: The Key to the Ageing Brain?

Greenwood

Brown

2021

IJMS

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Ageing represents the single biggest risk factor for development of neurodegenerative disease. Despite being such long-lived cells, microglia have been relatively understudied for their role in the ageing process. Reliably identifying aged microglia has proven challenging, not least due to the diversity of cell populations, and the limitations of available models, further complicated by differences between human and rodent cells. Consequently, the literature contains multiple descriptions and categorisations of microglia with neurotoxic phenotypes, including senescence, without any unifying markers. The role of microglia in brain homeostasis, particularly iron storage and metabolism, may provide a key to reliable identification.

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“…Moreover, ferrous iron could produce oxidation of lipids, proteins, and nucleic acid in astrocyte mitochondria [ 119 ]. Furthermore, an HO-1-dependent Fe accumulation in microglia has been reported to produce neuroinflammation in aged mice [ 120 ]. Importantly, the ZnPP administration or the use of HO-1 knockout mice prevented the increase of inflammatory markers in the same model [ 120 ].…”

Section: Therapeutic Implications Of Ho Inhibitorsmentioning

confidence: 99%

“…Furthermore, an HO-1-dependent Fe accumulation in microglia has been reported to produce neuroinflammation in aged mice [ 120 ]. Importantly, the ZnPP administration or the use of HO-1 knockout mice prevented the increase of inflammatory markers in the same model [ 120 ]. On the other hand, HO-1 overexpression in astrocytes induces a Parkinson´s disease-like phenotype [ 121 ].…”

Section: Therapeutic Implications Of Ho Inhibitorsmentioning

confidence: 99%

Immune Modulation by Inhibitors of the HO System

Fernández-Fierro

Funes

Ríos

et al. 2020

IJMS

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The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments.

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

Cited by 112 publications

References 79 publications

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

Senescent Microglia: The Key to the Ageing Brain?

Immune Modulation by Inhibitors of the HO System

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