MHC class II antigen expression and T-cell infiltration in the demyelinating CNS and PNS of the twitcher mouse

Ohno, Masaki; Komiyama, Atsushi; Martin, Parthena M.; Suzuki, Kinuko

doi:10.1016/0006-8993(93)91058-z

Cited by 39 publications

(30 citation statements)

References 53 publications

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“…The demyelinating effects of LPC are known to appear very rapidly in vitro as well as in vivo, and result from an increase in the hydrophilic nature of the molecular components of membranes, leading, in the case of myelin, to disruption of the intraperiod line, and finally to solubilization of the sheath (20). Elevated levels of psychosine elicit unique cellular reactions, such as formation of multinucleated cells (globoid cells) from resident microglia/macrophages, and reactive astrogliosis (52,53). Activated glial cells produce various inflammatory cytokines and related mediators (7,10,54) and chemokines, including macrophage chemoattractant protein-1, which are likely to play an important role in recruiting peripheral macrophages into the brain (54).…”

Section: Discussionmentioning

confidence: 99%

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Giri

Khan

Rattan

et al. 2006

Journal of Lipid Research

102

122

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Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside bgalactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose-and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.-Giri, S

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Section: Discussionmentioning

confidence: 99%

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Giri

Khan

Rattan

et al. 2006

Journal of Lipid Research

102

122

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“…Increased expression of MHC class II antigens, cytokines (TNF-α and IL-6), and inducible nitric oxide synthase have been reported in Krabbe and twi brains [8,9,11]. Indeed, nitric oxide [52] and TNF-α [53] are cytotoxic to oligodendrocytes and/or myelin in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Many advances in the understanding of the pathobiology of Krabbe disease have been in part possible to the availability of the twitcher mouse, an authentic murine model of the human disease [7]. The observed increased expression of the inflammatory cytokine Tumor Necrosis Factor-α (TNF-α brains from both Krabbe and twitcher [8,9], the inflammatory cytokine Interleukin-6 (IL-6), and the major histocompatibility antigens class I and II in twitcher brain [9][10][11], in addition of the presence of inducible nitric oxide synthase (iNOS)-expressing cells [12] and tunnel positive cells (apoptotic cells) in postmortem brain samples of Krabbe patients [13], indicate that local production of inflammatory cytokines may play a role in the apoptotic loss of oligodendrocytes in Krabbe and twitcher brains [14,15]. Studies from our laboratory indicate that psychosine enhances the expression of proinflammatory cytokine as well as that of iNOS, and hence the production of nitric oxide (NO) in primary cells culture [12].…”

Section: Introductionmentioning

confidence: 99%

Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Contreras

Haq

Uto

et al. 2008

Archives of Biochemistry and Biophysics

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Krabbe's disease is a neuroinflammatory disorder in which galactosylsphingosine (psychosine) accumulates in nervous tissue. To gain insight into whether the psychosine-induced effects in nervous tissue extend to peripheral organs, we investigated the expression of cytokines and their effects on peroxisomal structure/function in twitcher mouse liver (animal model of Krabbe disease). Immunofluorescence analysis demonstrated TNF-α and IL-6 expression, which was confirmed by mRNAs quantitation. Despite the presence of TNF-α, lipidomic analysis did not indicate a significant decrease in sphingomyelin or an increase in ceramide fractions. Ultrastructural analysis of catalasedependent staining of liver sections showed reduced reactivity without significant changes in peroxisomal contents. This observation was confirmed by assaying catalase activity and quantitation of its mRNA, both of which were found significantly decreased in twitcher mouse liver. Western blot analysis demonstrated a generalized reduction of peroxisomal matrix and membrane proteins. These observations indicate that twitcher mouse pathobiology extends to the liver, where the induction of TNF-α and IL-6 compromise peroxisomal structure and function.

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“…Demyelination in the twitcher is associated with massive infiltration of macrophages containing galactosylceramide inclusions but is not associated with other inflammatory cellular infiltrates. We have detected increased expression of Class II in macrophages/ microglia of this mutant with progression of demyelination (Higashi et al, 1992;Ohno et al, 1993). In twitcher mice on a Class II deficient background, demyelination and macrophage/microglial infiltration in the CNS appeared to be reduced (Matsushima et al, 1994), suggesting some role(s) of Class II in the demyelinating process in this mutant.…”

Section: Introductionmentioning

confidence: 86%

Expression of major histocompatibility complex class I antigens in the demyelinating twitcher CNS and PNS

et al. 1997

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MHC class II antigen expression and T-cell infiltration in the demyelinating CNS and PNS of the twitcher mouse

Cited by 39 publications

References 53 publications

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death

Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Expression of major histocompatibility complex class I antigens in the demyelinating twitcher CNS and PNS

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