Ferroptosis is an iron-dependent programmed cell death, regulated by specific pathways, in which iron dependentgeneration of lipid peroxidation products plays a key role. It is induced by severe oxidative stress and it has beendescribed in several neurodegenerative disorders, characterized by neuroinflammation.Multiple sclerosis (MS) is an autoimmune disease characterized by perivascular inflammation, demyelination,oligodendrocyte death, and neuronal degeneration. The mechanism of oligodendrocytes demise and sodemyelination, during the onset and progression of MS, has not yet been fully disclosed.To understand the potential link between ferroptosis and oligodendrocyte loss and demyelination, we analysedferroptosis induction and execution in human MO3.13 oligodendrocytes cell line (OLs), at the molecular level.Interestingly, we found that differentiated OLs are resistant to ferroptosis ‘independently from the stimulus ’,compared to immature cells. Mechanically, we found that mature OLs efficiently activate NRF2 which in turnupregulates the expression of aldo-keto reductase 1C1 (AKR1C1) that degrades lipid peroxides, thus conferringferroptotic cell death resistance. Indeed, inhibiting AKR1C1 activity/expression we completely resensitizeddifferentiated resistant OLs to ferroptosis execution.Importantly, we also found that both the pro-inflammatory cytokines TNF-α and IFN-ɤ, with a well-known diseasepromoting roles in MS, are able to sensitize mature OLs to ferroptosis through the downregulation of AKR1C1. Ourhypothesis is that the latter event could be mediated by miR-491, one of the miRNAs known to be expressed in theCNS of MS patients and targeting AKR1C1.Therefore, AKR1C1 might represent a new target for the treatment of MS since inhibiting its Cytokine/miRNA-dependent downregulation would protect mature OLs from ferroptotic dependent demise.

Pro-inflammatory cytokines and miRNA491 mediate the downregulation of AKR1C1 expression conferring oligodendrocytes sensitivity to ferroptotic cell death: potential implications for MS patients / Saverio, Valentina. - ELETTRONICO. - (2023).

Pro-inflammatory cytokines and miRNA491 mediate the downregulation of AKR1C1 expression conferring oligodendrocytes sensitivity to ferroptotic cell death: potential implications for MS patients

Saverio, Valentina
2023-01-01

Abstract

Ferroptosis is an iron-dependent programmed cell death, regulated by specific pathways, in which iron dependentgeneration of lipid peroxidation products plays a key role. It is induced by severe oxidative stress and it has beendescribed in several neurodegenerative disorders, characterized by neuroinflammation.Multiple sclerosis (MS) is an autoimmune disease characterized by perivascular inflammation, demyelination,oligodendrocyte death, and neuronal degeneration. The mechanism of oligodendrocytes demise and sodemyelination, during the onset and progression of MS, has not yet been fully disclosed.To understand the potential link between ferroptosis and oligodendrocyte loss and demyelination, we analysedferroptosis induction and execution in human MO3.13 oligodendrocytes cell line (OLs), at the molecular level.Interestingly, we found that differentiated OLs are resistant to ferroptosis ‘independently from the stimulus ’,compared to immature cells. Mechanically, we found that mature OLs efficiently activate NRF2 which in turnupregulates the expression of aldo-keto reductase 1C1 (AKR1C1) that degrades lipid peroxides, thus conferringferroptotic cell death resistance. Indeed, inhibiting AKR1C1 activity/expression we completely resensitizeddifferentiated resistant OLs to ferroptosis execution.Importantly, we also found that both the pro-inflammatory cytokines TNF-α and IFN-ɤ, with a well-known diseasepromoting roles in MS, are able to sensitize mature OLs to ferroptosis through the downregulation of AKR1C1. Ourhypothesis is that the latter event could be mediated by miR-491, one of the miRNAs known to be expressed in theCNS of MS patients and targeting AKR1C1.Therefore, AKR1C1 might represent a new target for the treatment of MS since inhibiting its Cytokine/miRNA-dependent downregulation would protect mature OLs from ferroptotic dependent demise.
2023
XXXV
Medical Sciences and Biotechnology
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11579/177382
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