Lactosylceramide Mediates the Expression of Adhesion Molecules in TNF-α and IFNγ-stimulated Primary Cultured Astrocytes

Astrocytes play complex roles in the response to trauma, infection or inflammation in the central nervous system (CNS). Thus, it is important to characterize the mechanisms regulating astrocyte function, as well as potential targets for the therapeutic modulation of astrocyte activity. Here we report that lactosylceramide (LacCer) levels are up-regulated in the CNS during chronic experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We found that LacCer synthesized by β-1,4-galactosyltransferase 6 (B4GALT6) in astrocytes acts in an autocrine manner to trigger transcriptional programs that promote the recruitment and activation of CNS-infiltrating monocytes and microglia, and neurodegeneration. We also detected increased B4GALT6 expression and LacCer levels in CNS MS lesions. Finally, the inhibition of LacCer synthesis suppressed local CNS innate immunity and neurodegeneration in EAE, and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 is a potential therapeutic target for MS and other neuroinflammatory disorders.

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“…LacCer is reported to activate NF-kB in astrocytes 18,26 and we confirmed these observations on astrocytes in vitro (Supplementary Fig. 7f).…”

Section: Resultssupporting

confidence: 88%

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Mayo¹,

Trauger²,

Blain³

et al. 2014

Nat Med

390

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“…Second, silencing of the lactosylceramide synthase gene in TNF-alpha and IFN-gamma-stimulated astrocytes attenuates the expression of adhesion molecules (e.g., intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1) that bind and recruit circulating T cells and monocytes. This is reversed by the addition of lactosylceramide [ 147 ]. Third, the depletion of glycosphingolipids by treatment with a series of sphingolipid synthesis inhibitors in cultured ECV-304 cells and Hela cells disrupt caveolin-1 high molecular weight oligomer formation [ 148 ] that promotes the transport of immune cells and antibodies across the barrier [ 149 ].…”

Section: Introductionmentioning

confidence: 99%

Glycosphingolipids and neuroinflammation in Parkinson’s disease

Bélarbi¹,

Cuvelier²,

Bonte³

et al. 2020

Mol Neurodegeneration

102

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Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson’s disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson’s disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson’s disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson’s disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson’s disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.

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“…Moreover, the STAT1 pathway can upregulate VCAM-1 and ICAM-1 independently of interferon-g (Duff et al, 1997;Stojanovic et al, 2009). There is evidence that STAT1 synergizes with NF-kΒ in inducing VCAM-1 and ICAM-1 (Jahnke and Johnson, 1994;Ohmori et al, 1997;Nizamutdinova et al, 2009;Lee et al, 2011) and that GITRL triggering activates the noncanonical pathway leading to NF-kΒ activation (Grohmann et al, 2007). In our experimental model, it is likely that NF-kΒ is already activated due to treatment with TNF-a (Mackay et al, 1993) and GITRL-dependent-NF-kΒ-activation might synergize with TNF-a in potentiating the upregulation of adhesion molecules.…”

Section: Discussionmentioning

confidence: 89%

“…Indeed, induction of adhesion molecule expression and cell adhesion through a STAT1-dependent pathway has been previously described in response to interferon-g Lee et al, 2011). Moreover, the STAT1 pathway can upregulate VCAM-1 and ICAM-1 independently of interferon-g (Duff et al, 1997;Stojanovic et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Ligand Triggering Upregulates Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 and Promotes Leukocyte Adhesion

Lacal

Petrillo

Ruffini

et al. 2013

J Pharmacol Exp Ther

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The interaction of glucocorticoid-induced tumor necrosis factor receptor-family related (GITR) protein with its ligand (GITRL) modulates different functions, including immune/inflammatory response. These effects are consequent to intracellular signals activated by both GITR and GITRL. Previous results have suggested that lack of GITR expression in GITR 2/2 mice decreases the number of leukocytes within inflamed tissues. We performed experiments to analyze whether the GITRL/GITR system modulates leukocyte adhesion and extravasation. For that purpose, we first evaluated the capability of murine splenocytes to adhere to endothelial cells (EC). Our results indicated that adhesion of GITR 2/2 splenocytes to EC was reduced as compared with wild-type cells, suggesting that GITR plays a role in adhesion and that this effect may be due to GITRL-GITR interaction. Moreover, adhesion was increased when EC were pretreated with an agonist GITR-Fc fusion protein, thus indicating that triggering of GITRL plays a role in adhesion by EC regulation. In a human in vitro model, the adhesion to human EC of HL-60 cells differentiated toward the monocytic lineage was increased by EC pretreatment with agonist GITRFc. Conversely, antagonistic anti-GITR and anti-GITRL Ab decreased adhesion, thus further indicating that GITRL triggering increases the EC capability to support leukocyte adhesion. EC treatment with GITR-Fc favored extravasation, as demonstrated by a transmigration assay. Notably, GITRL triggering increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and anti-ICAM-1 and anti-VCAM-1 Abs reversed GITR-Fc effects. Our study demonstrates that GITRL triggering in EC increases leukocyte adhesion and transmigration, suggesting new antiinflammatory therapeutic approaches based on inhibition of GITRL-GITR interaction.

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Lactosylceramide Mediates the Expression of Adhesion Molecules in TNF-α and IFNγ-stimulated Primary Cultured Astrocytes

Cited by 11 publications

References 30 publications

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

Glycosphingolipids and neuroinflammation in Parkinson’s disease

Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Ligand Triggering Upregulates Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 and Promotes Leukocyte Adhesion

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