Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells.
Sulfatide, a major lipid component of myelin sheath, participates in diverse cellular events of the CNS, and its cellular level has recently been implicated in many inflammation-associated neuronal diseases. Herein, we report that sulfatide alone can trigger pathological inflammatory responses in glia, brain-resident immune cells. We show that sulfatide changed the morphology of primary microglia to their activated form, and it significantly induced the production of various inflammatory mediators in primary microglia and astrocytes. Moreover, sulfatide rapidly triggered the phosphorylation of p38, ERK, and JNK within 30 min, and it markedly enhanced the NF binding activity to NF-kappaB and AP-1 binding elements. However, nonsulfated galactocerebroside, another major lipid component of myelin, had no effect on activation of glia. We further reveal that CD1d did not contribute to sulfatide-stimulated activation of MAPKs, although its expression was enhanced by sulfatide and sulfatide-treated microglial cells actually stimulated type II NKT cells. Sulfatide significantly stimulated the phosphorylation of MAPKs in glia from CD1d-deficient mice, and the phosphorylation levels were similar to those in wild-type littermates. Sulfatide-triggered inflammatory events appear to occur at least in part through an L-selectin-dependent mechanism. L-selectin was dramatically down-regulated upon exposure to sulfatide, and inhibition of L-selectin resulted in suppression of sulfatide-triggered responses. Collectively, these results show that abnormally released sulfatide at demyelinated regions may act as an endogenous stimulator in the brain immune system, thus causing and further exacerbating pathological conditions in the brain.
Jeon
Sae-Bom
SB
Immune and Cell Therapy Branch, National Cancer Center, Goyang, Korea.
Yoon
Hee Jung
HJ
Park
Se-Ho
SH
Kim
In-Hoo
IH
Park
Eun Jung
EJ
D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000737:chemistry* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013433:Sulfoglycosphingolipids / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D018836:Inflammation Mediators; D016328:NF-kappa B; D013433:Sulfoglycosphingolipids; D018808:Transcription Factor AP-1; D019041:L-Selectin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4