Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Ryan, Sean K.; Zelic, Matija; Han, Yingnan; Teeple, Erin; Chen, Luoman; Sadeghi, Mahdiar; Shankara, Srinivas; Guo, Lilu; Liu, Cong; Pontarelli, Fabrizio; Jensen, Elizabeth H.; Kumar, Dinesh; Zhang, Mindy; Gans, Joseph H.; Zhang, Bailin; Proto, Jonathan D.; Saleh, Jacqueline; Dodge, James C.; Rajpal, Deepak K.; Ofengeim, Dimitry; Hammond, Timothy R.

doi:10.1101/2021.11.02.466996

Cited by 3 publications

(6 citation statements)

References 61 publications

(77 reference statements)

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“…PM were the most susceptible to ferroptosis in both monoculture and tri-culture systems. These results were consistent with that microglia possessed the highest susceptibility to ferroptosis in a human iPSC-derived tri-culture system which consists of a relative percentage of astrocytes, microglia, and neurons (Ryan et al, 2021).…”

Section: Discussionsupporting

confidence: 88%

Iron metabolism mediates microglia susceptibility in ferroptosis

Jiao

Luo

et al. 2022

Front. Cell. Neurosci.

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Ferroptosis is implicated in a range of brain disorders, but it is unknown whether neurons or glia in the brain are particularly effected. Here, we report that primary cortical astrocytes (PA), microglia (PM), and neurons (PN) varied in their sensitivities to ferroptosis. Specifically, PM were the most sensitive to ferroptosis, while PN were relatively insensitive. In contrast, PN and PM were equally susceptible to apoptosis, with PA being less affected, whereas all three cell types were similarly susceptible to autophagic cell death. In the tri-culture system containing PA, PM, and PN, the cells were more resistant to ferroptosis than that in the monoculture. These results demonstrated that brain cells exhibit different sensitivities under ferroptosis stress and the difference may be explained by the differentially regulated iron metabolism and the ability to handle iron. Continued elucidation of the cell death patterns of neurons and glia will provide a theoretical basis for related strategies to inhibit the death of brain cells.

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Section: Discussionsupporting

confidence: 88%

Iron metabolism mediates microglia susceptibility in ferroptosis

Jiao

Luo

et al. 2022

Front. Cell. Neurosci.

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“…This proposition is supported by our findings that microglia – the resident immune cells of the CNS – are more sensitive to ferroptosis than astrocytes or neurones in vitro ( Fig. 2 ), an observation in line with recent gene expression data (58). When ferroptotic stress insufficient to induce cell death is applied to microglia, it triggers an inflammatory response that induces a neurotoxic glial phenotype ( Fig.…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

“…4a ); 3) lipoxygenases are involved in intitiation of ferroptosis (40) and their specific expression by microglia in the CNS may contribute to the greater sensitivity of microglia to ferroptosis ( Fig. 2 ); and 4) microglial gene expression changes identified by RNAseq in response to ferroptotic stimuli are evident in human ALS-affected spinal cord (58). Together, these data indicate that the emergence of ferroptotic stimuli in vivo , as evident in ALS, causes preferential inflammatory activation of microglia that induces neurotoxic activation of astrocytes and neuronal death.…”

Section: Discussionmentioning

confidence: 99%

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Microglial ferroptotic stress causes non-cell autonomous neuronal death

Liddell

Hilton

Kysenius

et al. 2022

Preprint

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BackgroundFerroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.MethodsTo elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). Finally, we utilised the SOD1G37R mouse model of ALS and a novel CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.ResultsWe found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Moreover, a molecular correlation between ferroptosis and neurotoxic astrocytes evident in ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with the novel, CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective.ConclusionsBy showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

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“…Ferroptosis is involved in neuronal cell death generated by adult ischemia and intraventricular hemorrhage, and suppression of the ferroptosis protects the neuronal cell from death [ 30 , 36 , 39 , 40 ]. Nevertheless, despite the fact that there have only been a few studies demonstrating ferroptosis regarding neonatal brain injury, the evidence implies that ferroptosis would more likely occur in the neonatal brain [ 41 – 43 ].…”

Section: Introductionmentioning

confidence: 99%

Microglial iron trafficking: new player in brain injury

Keleş¹,

Kazan²,

Aral³

et al. 2022

Turkish Journal of Medical Sciences

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Neonatal brain injury is a significant reason of neurodevelopmental abnormalities and long-term neurological impairments. Hypoxic-ischemic encephalopathy and preterm brain injury, including intraventricular hemorrhage are the most common grounds of brain injury for full-term and preterm neonates. The prevalence of hypoxic ischemic encephalopathy varies globally, ranging from 1 to 3.5/1000 live births in high-resource countries and 26/1000 in low-resource countries. Preterm birth’s global incidence is 15 million, a significant reason for infant mortality and morbidity, permanent neurologic problems, and the associated social and economic burden. The widespread neurodevelopmental effects of neonatal brain injury could have an unfavorable impact on a variety of aspects of cognitive, linguistic, behavioral, sensory, and motor functions. Brain injury occurs via various mechanisms, including energy deprivation, excitatory amino acids, mitochondrial dysfunction, reactive oxygen species, and inflammation giving rise to different forms of cell death. The contribution of microglial activity in neonatal brain injury has widely been underlined by focusing on cell death mechanisms since the neuronal death pathways during their development are distinct from those in the adult brain. Iron accumulation and lipid peroxidation cause a relatively novel type of regulated cell death called ferroptosis. Neonates generally have biochemical iron inequalities, and their antioxidant potential is highly restricted, implying that ferroptosis may be significant in pathologic conditions. Moreover, inhaled nitric oxide therapy in infants may lead to microglial inflammation via ferroptosis and neuronal injury in the developing brain. This review article aims to summarize the studies that investigated the association between neonatal brain injury and iron metabolism, with a particular emphasis on the microglial activity and its application to the inhibition of neonatal brain injury.

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Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Cited by 3 publications

References 61 publications

Iron metabolism mediates microglia susceptibility in ferroptosis

Iron metabolism mediates microglia susceptibility in ferroptosis

Microglial ferroptotic stress causes non-cell autonomous neuronal death

Microglial iron trafficking: new player in brain injury

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