Aberrant Upregulation of Astroglial Ceramide Potentiates Oligodendrocyte Injury

Abstract

Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis and periventricular leukomalacia. Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of multiple sclerosis and periventricular leukomalacia, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination and revealed a concomitant increase of sphingosine as well as a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders.

Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglioma cell line

“…However, our observations that exogenous C6-Cer or C16-Cer mimic and further enhance the cytotoxic effects of the cytokines are in support of the role of Cer per se as a contributor to cell death response. This is consistent with previous studies showing that exogenous Cer could induce apoptosis in the same time frame and kill HOG cells as effectively as TNF- (11) and that an upregulation of Cer was linked to oligodendrocyte cell injury (44,45). It is also known that many of the toxic effects of TNF- in diverse cell types occur through generation of C16:0-Cer, and that these effects can be reversed by a reduction in this Cer (46,47).…”

“…We envision that shedding of Cers may promote the autoimmune response that occurs under demyelinating conditions in the central nervous system. There is evidence for an accumulation of Cer species, including C16:0-, C18:0-, C18:1-, C24:0-, and C24:1-Cer, in multiple sclerosis plaques and/or animal models of the disease (44,45,51), as well as increased levels of C16:0-and C24:0-Cer in the multiple sclerosis cerebrospinal fluid (52). However, with respect to such in vivo significance of our present findings, it would be important to first verify the phenomenon of exosome-mediated cell death signaling in primary oligodendrocytes prior to its in vivo validation.…”

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

“…Astrocyte production of IL-15 leads to the activation of CD8 T-lymphocytes that contribute to the exacerbation of tissue damage during MS [34] . Recent studies also suggest that aberrant upregulation of astroglial ceramide potentiates OL injury [35,36] . In the present study, we found hypertrophic and hyperplastic as- The open-field test has been used to assess motor and psychiatric behavioral deficits, including spontaneous locomotion and exploratory activity in a novel environment [37,38] .…”

Galectin-9 Protein Is Up-regulated in Astrocytes by Tumor Necrosis Factor and Promotes Encephalitogenic T-cell Apoptosis

“…The neuron cultures underwent a total of 3 cycles of 5-fluorodeoxyuridine treatment and were cultured in NBB27 medium for 2-3 weeks. The purity of our primary cultures was characterized previously (16,19,20) and assessed again from two independent experiments in this study by immunohistochemistry using antibodies specific for astrocytes (GFAP), microglia (Iba-1), oligodendrocytes (O4), and neurons (MAP2) and DAPI counterstain. Astrocyte cultures were greater than 94% GFAP ϩ , oligodendrocytes were greater than 92% O4 ϩ , and microglia cultures were greater than 95% Iba-1 ϩ .…”