Pathological Involvement of Astrocyte-Derived Lipocalin-2 in the Demyelinating Optic Neuritis

Chun, Bo Young; Kim, Jong‐Heon; Nam, Youngpyo; Huh, Man-Il; Han, Seung-Woo; Suk, Kyoungho

doi:10.1167/iovs.15-16851

Cited by 37 publications

(32 citation statements)

References 34 publications

(33 reference statements)

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“…Using a microarray, conditional knockout, in vitro manipulation of oligodendrocyte lineage cells, and ex vivo/in vivo modeling of remyelination, we uncovered the inhibitory effects of LCN2 and activated EGR1 on appropriate oligodendrocyte differentiation in WMI. These findings extend previous studies that did not find an effect of LCN2 on myelin (Chun et al, 2015;Nam et al, 2014), by demonstrating a direct and disease-relevant role in oligodendrocyte lineage cells. Our results also extend the list of negative regulators of oligodendroglial differentiation to now include the regulation of myelin repair and the appropriate response to WMI in human disease (Kremer et al, 2011).…”

Section: Discussionsupporting

confidence: 90%

“…Having shown the positive effects of LCN2 reticence on functional recovery after WMI, we next asked whether the inhibition of LCN2 could promote remyelination. Previous work showed that LCN2 contributes to demyelination in MS, spinal cord injury and optic neuritis, as well as SAH 9 (Chun et al, 2015;Khalil et al, 2016;Rathore et al, 2011). We also found that the inhibition of LCN2 reduced the expression of degraded myelin basic protein (DMBP), a biomarker of demyelination, while regulating MBP in the white matter of LCN2 KD mice after SAH (Online Resource Supplemental Fig.…”

Section: Wmimentioning

confidence: 56%

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Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Yang

et al. 2020

Preprint

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The insufficient remyelination due to the impaired oligodendrocyte precursor cell differentiation and maturation is highly associated with irreversible white matter injury and neurological deficits. Consequently, inhibitory components and microenvironment for remyelination might serve as potential therapeutic targets for treating white matter injury after acute central nervous system injury and neurodegeneration diseases. Lipocalin-2 was recently reported to corelate with white matter in both atypical, acute white matter injured disease subarachnoid hemorrhage and typical, chronic white matter injured disease multiple sclerosis. To elucidate the role and underlying mechanism of Lipocalin-2 in oligodendrocyte precursor cell differentiation and remyelination, we used genetic inhibition and a constitutive conditional knockout model with subarachnoid hemorrhage or multiple sclerosis. We found that the genetic inhibition of the increase in Lipocalin-2 promoted oligodendrocyte precursor cell differentiation, remyelination, and functional recovery after subarachnoid hemorrhage or multiple sclerosis. Unexpectedly, the inhibition of Lipocalin-2 did not reduce glial activation and inflammation. Lipocalin-2 was shown to activate Early Growth Response Protein 1 in oligodendrocyte precursor cells, which is partly regulated by its receptor SLC22A17. In the conditional knockout of Early Growth Response Protein 1 in oligodendrocyte precursor cells, we discovered enhanced oligodendrocyte precursor cell differentiation in developing and 4 injured white matter; consistently, the specific inactivation of Early Growth Response Protein 1 promoted remyelination and neurological recovery after subarachnoid hemorrhage or multiple sclerosis. Thus, we propose that following white matter injury in humans, the increase in Lipocalin-2 activates Early Growth Response Protein 1 and consequently impair oligodendrocyte precursor cell differentiation and myelin repair. Our results suggest that therapies specifically inactivating Lipocalin-2/ Early Growth Response Protein 1 signal in oligodendroglial lineage cells could represent a novel strategy to enhance differentiation and remyelination in white matter injury patients.

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Section: Discussionsupporting

confidence: 90%

Section: Wmimentioning

confidence: 56%

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Yang

et al. 2020

Preprint

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“…Thus, LCN2 is a powerful inducer of chemokines and causes an upregulation of CXCL10 through JAK2/STAT3 and IKK/NF‐κB pathways . The significance of increased levels of LCN2 for white matter damage of optic nerves was demonstrated with LCN2 KO mice, which have much more limited damage in experimental autoimmune optic neuritis .…”

Section: Murine Models Of Axdmentioning

confidence: 99%

Alexander disease: an astrocytopathy that produces a leukodystrophy

2018

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Alexander Disease (AxD) is a degenerative disorder caused by mutations in the GFAP gene, which encodes the major intermediate filament of astrocytes. As other cells in the CNS do not express GFAP, AxD is a primary astrocyte disease. Astrocytes acquire a large number of pathological features, including changes in morphology, the loss or diminution of a number of critical astrocyte functions and the activation of cell stress and inflammatory pathways. AxD is also characterized by white matter degeneration, a pathology that has led it to be included in the "leukodystrophies." Furthermore, variable degrees of neuronal loss take place. Thus, the astrocyte pathology triggers alterations in other cell types. Here, we will review the neuropathology of AxD and discuss how a disease of astrocytes can lead to severe pathologies in non-astrocytic cells. Our knowledge of the pathophysiology of AxD will also lead to a better understanding of how astrocytes interact with other CNS cells and how astrocytes in the gliosis that accompanies many neurological disorders can damage the function and survival of other cells.

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“…For example, LCN-2 expression was increased > 80 fold in the ganglion cells following optic nerve crush-a popular model for glaucoma and neuronal apoptosis due to axonal degeneration [102]. LCN-2 was also found to regulate inflammation in the optic nerve during the progression of optic neuritis [103]. Optic neuritis is frequently the first clinical manifestation of multiple sclerosis, and is characterized by acute self-limiting inflammation of the optic nerve associated with demyelination of the retinal ganglion cell axons and decreased visual acuity.…”

Section: Role Of Lcn-2 In Ocular Diseases: Focus On Age-related Maculmentioning

confidence: 99%

“…LCN-2 immunostaining co-localized with the astrocyte-specific marker glial fibrillary acidic protein (GFAP), suggesting that reactive astrocytes are the main sources of LCN-2 in the inflamed optic nerves. The authors speculate that the lack of the classical blood-brain-barrier properties of the optic nerve (compared to the retina) may facilitate the recruitment of immune cells and development of inflammation [103].…”

Section: Role Of Lcn-2 In Ocular Diseases: Focus On Age-related Maculmentioning

confidence: 99%

The role of lipocalin-2 in age-related macular degeneration (AMD)

Ghosh

Stepicheva

Yazdankhah

et al. 2020

Cell. Mol. Life Sci.

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Lipocalins are a family of secreted adipokines which play important roles in various biological processes. Lipocalin-2 (LCN-2) has been shown to be involved in acute and chronic inflammation. This particular protein is critical in the pathogenesis of several diseases including cancer, diabetes, obesity, and multiple sclerosis. Herein, we discuss the general molecular basis for the involvement of LCN-2 in acute infections and chronic disease progression and also ascertain the probable role of LCN-2 in ocular diseases, particularly in age-related macular degeneration (AMD). We elaborate on the signaling cascades which trigger LCN-2 upregulation in AMD and suggest therapeutic strategies for targeting such pathways.Keywords Lipocalin-2 (LCN-2) · Age-related macular degeneration (AMD) · Inflammation · AKT2 signaling · Retinal degeneration Cellular and Molecular Life SciencesElectronic supplementary material The online version of this article (https ://doi.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Pathological Involvement of Astrocyte-Derived Lipocalin-2 in the Demyelinating Optic Neuritis

Cited by 37 publications

References 34 publications

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

Alexander disease: an astrocytopathy that produces a leukodystrophy

The role of lipocalin-2 in age-related macular degeneration (AMD)

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