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

Steelman, Andrew J.; Smith, Roger; Welsh, C. Jane; Li, Jianrong

doi:10.1074/jbc.m113.451658

Cited by 60 publications

(58 citation statements)

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“…Similar responses were observed following LPS stimulation (Additional file 3: Figure S3A and B). In line with our previous results [36], microglia constitutively expressed Lgals9 (Figure 2B). However, in mixed glial cultures poly(I:C) time-dependently induced EGFP expression in cells morphologically resembled astrocytes (Figure 2D), a finding that was further confirmed by immunocytochemical analysis, which revealed co-localization of GFP + cells with GFAP + astrocytes (Figure 2E).…”

Section: Resultssupporting

confidence: 93%

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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Section: Resultssupporting

confidence: 93%

Astrocyte galectin-9 potentiates microglial TNF secretion

Steelman

2014

J Neuroinflammation

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“…Moreover, individual factors mimicking or associated with inflammatory stress, such as LPS, IFN-c, TNF, and IL-1b, are powerful stimuli for galectin-9 expression in a variety of cells, including vascular endothelial cells [133,134], monocytes [135], macrophages [136], fibroblasts [137], multipotent mesenchymal stromal cells [138], and astrocytes [139,140]. A variety of transcription factors and related signaling pathways have been reported to be essential for the upregulation of galectin-9, including a redox-sensitive JNK/c-Jun signaling pathway in astrocytes [140], the phosphorylation of STAT-1 in HUVEC cells [141], and Smad3 in regulatory T cells [142]. Although it remains unclear how galectin-9 collaborates with other galectins, the administration of the recombinant galectin-9 seems to be a very promising strategy for treating immune and cancer diseases [131].…”

Section: Galectin-9mentioning

confidence: 99%

Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions

Timoshenko

2015

Cell. Mol. Life Sci.

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Galectins, a family of soluble β-galactoside-binding proteins, serve as mediators of fundamental biological processes, such as cell growth, differentiation, adhesion, migration, survival, and death. The purpose of this review is to summarize the current knowledge regarding the ways in which the expression of individual galectins differs in normal and transformed human cells exposed to various stimuli mimicking physiological and pathological microenvironmental stress conditions. A conceptual point is being made and grounded that the modulation of galectin expression profiles is a key aspect of cellular stress responses. Moreover, this modulation might be precisely regulated at transcriptional and post-transcriptional levels in the context of non-overlapping transcription factors and miRNAs specific to galectins.

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“…Expression levels for Tim-3 and galectin-9 were shown to be correlated positively during infections [37,40]. In CNS, galectin-9 is undetectable on astrocyte, but it can be up-regulated by IL-1, IFN-c and TNF [41][42][43], and is significantly elevated on astrocytes present in MS lesions [7]. Therefore it is possible that neighboring cells might play a role in regulating the activity of microglia in both normal and pathological conditions through expression of galectin-9.…”

Section: Discussionmentioning

confidence: 97%