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Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells¹

Sae-Bom Jeon^*,, Hee Jung Yoon^*, Se-Ho Park, In-Hoo Kim^2, and Eun Jung Park^2,*

^* Immune and Cell Therapy Branch, National Cancer Center, Goyang, Korea; Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, Korea; Graduate School of Life Sciences and Biotechnology, Korea University, Seoul, Korea; and Molecular Imaging and Therapy Branch, National Cancer Center, Goyang, Korea

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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Cancer Center (0710320), Korea Research Foundation Grant funded by the Korean Government (KRF-2005-041-E00103), and by RO1-2006-000-10314-0 from the Basic Research Program of the Korea Science and Engineering Foundation.

² Address correspondence and reprint requests to Dr. Eun Jung Park, Immune and Cell Therapy Branch, National Cancer Center, Goyang 410-769, Korea. E-mail address: ejpark{at}ncc.re.kr or Dr. In-Hoo Kim, Molecular Imaging and Therapy Branch, National Cancer Center, Goyang 410-769, Korea. E-mail address: ihkim{at}ncc.re.kr

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; iNOS, inducible NO synthase; MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; SOCS, suppressor of cytokine signaling.