The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

Tassoni, Alessia; Farkhondeh, Vista; Itoh, Yuichiro; Itoh, Noriko; Sofroniew, Michael V.; Voskuhl, Rhonda R.

doi:10.1038/s41598-019-46232-6

Cited by 61 publications

(86 citation statements)

References 60 publications

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“…Since sex hormones and sex chromosomes would not act homogeneously across cells in the entire brain, differential effects on cells in specific CNS regions can be missed when examining whole GM or whole cerebral cortex. We previously hypothesized that sex differences in neurodegeneration in MS would be region-specific [33,35,36], and our data here on sex differences in GM atrophy are consistent with this hypothesis.…”

Section: Correlations Between 9hpt and Subcortical Gm Volumessupporting

confidence: 89%

Sex differences in brain atrophy in multiple sclerosis

et al. 2020

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Background: Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age-and sexmatched healthy controls. Methods: Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. Results: VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. Conclusion: More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.

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Section: Correlations Between 9hpt and Subcortical Gm Volumessupporting

confidence: 89%

Sex differences in brain atrophy in multiple sclerosis

et al. 2020

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“…These findings broaden our understanding of astrocyte heterogeneity in the CNS. Although regional heterogeneity of astrocytes in neurophysiologic functions (18, 19, 105) and in many disease models (106-108), including EAE (75, 109, 110), has been appreciated, there are no studies to date that have described a regional role for the iP in the CNS. However, a regional difference in Type I IFN signaling in astrocytes has been described (111).…”

Section: Discussionmentioning

confidence: 99%

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Sinyuk

et al. 2019

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17In early autoimmune neuroinflammation, interferon (IFN)g and its upregulation of the 18 immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNg has 19 protective properties and, the role of the iP remains to be fully elucidated. Here, we demonstrated 20 that IFNg signaling in regional astrocytes induces the iP and protects the CNS during 21 autoimmunity. In MS tissue, iP expression was enhanced in spinal cord compared to brainstem 22 lesions, which correlated with a decrease in oxidative stress. In vitro, IFNg stimulation enhanced 23 iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and 24 poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was 25 abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal 26 model, experimental autoimmune encephalomyelitis (EAE), ONX 0914 treatment exacerbated 27 disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice 28 with astrocyte-specific loss of the IFNg receptor exhibited worsened chronic EAE associated with 29 reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein 30 accumulation in astrocytes. Taken together, our data reveal a protective role for IFNg in chronic 31 neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity. 32 33 34 Multiple sclerosis (MS) is the most common chronic inflammatory and 35 neurodegenerative disease of the central nervous system (CNS) (1). During the 36 pathogenesis of MS, there is immune cell infiltration, demyelination, and reactive gliosis 37within CNS lesions in multiple regions (2). Relapsing-remitting MS (RRMS) is a subtype 38 that affects approximately 85% of patients and is characterized by episodic periods of 39 neurological dysfunction, often associated with inflammation, followed by partial or 40 complete recovery. A significant proportion of these patients go on to develop secondary 41 progressive MS (SPMS), during which they have fewer remissions and increasing 42 atrophy, correlating with progressive disability (3, 4). Primary progressive (PPMS) a third 43 subtype of MS, affects approximately 15% of patients and is associated with continuous, 44 progressive loss of neurological function after initial diagnosis, without periods of 45 remission (5, 6). Of note, it is thought that the pathology associated with RRMS has a 46 relatively significant inflammatory component, while in SPMS and PPMS, inflammation is 47 an animal model of MS, astrocytes are known to exhibit regional heterogeneity in gene 58 expression and response to inflammation (17)(18)(19). Indeed, ablation of astrocytes following 59 several types of CNS injury leads to sustained inflammation, impaired repair, and 60 increased neurodegeneration (20-29), suggesting that a diverse astrocytic response is 61 critical in healthy tissue preservation and support, minimizing CNS bystander damage 62 during...

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“…NMOSD are a class of disorders that also present with optic neuritis or transverse myelitis (71), but are usually characterized by an antibody to aquaporin 4, which is expressed by astrocytes (83). In models of optic neuritis, astrocytes in the optic nerve express C3 (121), which also deposits on discarded myelin either directly or through complement-activating anti-MOG antibodies (84). In NMOSD models, although these antibodies do not directly bind myelin or oligodendrocytes, microglia/macrophages still phagocytose myelin debris (122).…”

Section: Complement In Demyelinating Diseasesmentioning

confidence: 99%

Complement-Mediated Microglial Phagocytosis and Pathological Changes in the Development and Degeneration of the Visual System

et al. 2020

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The focus of this review is the role of complement-mediated phagocytosis in retinal and neurological diseases affecting the visual system. Complement activation products opsonize synaptic material on neurons for phagocytic removal, which is a normal physiological process during development, but a pathological process in several neurodegenerative diseases and conditions. We discuss the role of complement in the refinement and elimination of synapses in the retina and lateral geniculate nucleus, both during development and in disease states. How complement and aberrant phagocytosis promotes injury to the visual system is discussed primarily in the context of multiple sclerosis, where it has been extensively studied, although the role of complement in visual dysfunction in other diseases such as stroke and traumatic brain injury is also highlighted. Retinal diseases are also covered, with a focus on glaucoma and age-related macular degeneration. Finally, we discuss the potential of complement inhibitory strategies to treat diseases affecting the visual system.

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The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

Cited by 61 publications

References 60 publications

Sex differences in brain atrophy in multiple sclerosis

Sex differences in brain atrophy in multiple sclerosis

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

Complement-Mediated Microglial Phagocytosis and Pathological Changes in the Development and Degeneration of the Visual System

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