Increased expression of distinct galectins in multiple sclerosis lesions

Stancic, Mirjana; Horssen, Jack van; Thijssen, Victor L.; Gabius, Hans‐Joachim; Valk, P. van der; Hoekstra, Dick; Baron, Wia

doi:10.1111/j.1365-2990.2011.01184.x

Cited by 74 publications

(62 citation statements)

References 60 publications

(67 reference statements)

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“…The involvement of Gal-9 in modulating the neuroinflammatory events in MS are supported by several lines of evidence. First, Gal-9 expression is increased in MS lesions (13,14). Second, the Gal-9 receptor, Tim-3, is dysregulated on T-cells isolated from the circulation of MS patients, thereby rendering the T-cells less susceptible to the immunoregulatory outcomes after Gal-9 ligation (15).…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

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

Steelman¹,

Smith

Welsh

et al. 2013

Journal of Biological Chemistry

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Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

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

Steelman¹,

Smith

Welsh

et al. 2013

Journal of Biological Chemistry

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“…Gal-3 has been implicated in MS; it is expressed at high levels in active lesions around the lateral ventricles, and it modulates animal models of MS [16, 23]. Gal-3 was initially termed Mac-2 because it was identified in activated macrophages [24].…”

Section: Introductionmentioning

confidence: 99%

Cuprizone demyelination induces a unique inflammatory response in the subventricular zone

Hillis

Davies

Mundim

et al. 2016

J Neuroinflammation

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BackgroundCuprizone leads to demyelination of the corpus callosum (CC) and activates progenitor cells in the adjacent subventricular zone (SVZ), a stem cell niche which contributes to remyelination. The healthy SVZ contains semi-activated microglia and constitutively expresses the pro-inflammatory molecule galectin-3 (Gal-3) suggesting the niche uniquely regulates inflammation.MethodsWe studied the inflammatory response to cuprizone in the SVZ and CC in Gal-3 knockout mice using immunohistochemistry and with the in vitro neurosphere assay.ResultsCuprizone caused loss of myelin basic protein (MBP) immunofluorescence in the CC suggesting demyelination. Cuprizone increased the density of CD45+/Iba1+ microglial cells and also increased Gal-3 expression in the CC. Surprisingly, the number of Gal-3+ and CD45+ cells decreased in the SVZ after cuprizone, suggesting inflammation was selectively reduced therein. Inflammation can regulate SVZ proliferation and indeed the number of phosphohistone H3+ (PHi3+) cells decreased in the SVZ but increased in the CC in both genotypes after cuprizone treatment. BrdU+ SVZ cell numbers also decreased in the SVZ after cuprizone, and this effect was significantly greater at 3 weeks in Gal-3−/− mice compared to WT, suggesting Gal-3 normally limits SVZ cell emigration following cuprizone treatment.ConclusionsThis study reveals a uniquely regulated inflammatory response in the SVZ and shows that Gal-3 participates in remyelination in the cuprizone model. This contrasts with more severe models of demyelination which induce SVZ inflammation and suggests the extent of demyelination affects the SVZ neurogenic response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0651-2) contains supplementary material, which is available to authorized users.

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“…Studies in vitro have shown that galectin-9 can induce maturation of human monocyte-derived dendritic cells [33] and enhance proinflammatory cytokine secretion [34], which have been attributable to its ability to bind the highly glycosylated T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) [34]. While galectin-9 protein or the gene encoding galectin-9, Lgals9 , is not normally expressed at high levels within the CNS [35,36], it is increased following experimental pneumococcal meningitis [37] as well as infection with herpes simplex virus [38] or Japanese encephalitis virus [39] and is reportedly increased in the brains of multiple sclerosis patients [34,40], indicating that it becomes up-regulated during inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

Astrocyte galectin-9 potentiates microglial TNF secretion

Steelman

2014

J Neuroinflammation

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BackgroundAberrant neuroinflammation is suspected to contribute to the pathogenesis of myriad neurological diseases. As such, determining the pathways that promote or inhibit glial activation is of interest. Activation of the surface glycoprotein T-cell immunoglobulin and mucin-domain containing protein 3 (Tim-3) by the lectin galectin-9 has been implicated in promoting innate immune cell activation by potentiating or synergizing toll-like receptor (TLR) signaling. In the present study we examined the role of the Tim-3/galectin-9 pathway in glial activation in vitro.MethodPrimary monocultures of microglia or astrocytes, co-cultures containing microglia and astrocytes, and mixed glial cultures consisting of microglia, astrocytes and oligodendrocytes were stimulated with poly(I:C) or LPS, and galectin-9 up-regulation was determined. The effect of endogenous galectin-9 production on microglial activation was examined using cultures from wild-type and Lgals9 null mice. The ability for recombinant galectin-9 to promote microglia activation was also assessed. Tim-3 expression on microglia and BV2 cells was examined by qPCR and flow cytometry and its necessity in transducing the galectin-9 signal was determined using a Tim-3 specific neutralizing antibody or recombinant soluble Tim-3.ResultAstrocytes potentiated TNF production from microglia following TLR stimulation. Poly(I:C) stimulation increased galectin-9 expression in microglia and microglial-derived factors promoted galectin-9 up-regulation in astrocytes. Astrocyte-derived galectin-9 in turn enhanced microglial TNF production. Similarly, recombinant galectin-9 enhanced poly(I:C)-induced microglial TNF and IL-6 production. Inhibition of Tim-3 did not alter TNF production in mixed glial cultures stimulated with poly(I:C).ConclusionGalectin-9 functions as an astrocyte-microglia communication signal and promotes cytokine production from microglia in a Tim-3 independent manner. Activation of CNS galectin-9 likely modulates neuroinflammatory processes in which TNF and IL-6 contribute to either pathology or reparation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0144-0) contains supplementary material, which is available to authorized users.

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Increased expression of distinct galectins in multiple sclerosis lesions

Abstract: This study provides a detailed analysis of galectins in MS lesions and assigns distinct galectins to different aspects of the disease. Thus, besides being known as modulators of inflammatory processes, our findings suggest additional association of distinct galectins with MS pathology.

Cited by 74 publications

References 60 publications

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

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

Cuprizone demyelination induces a unique inflammatory response in the subventricular zone

Astrocyte galectin-9 potentiates microglial TNF secretion

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