Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation

被引：349

作者：

Mayo, Lior ^{[1
]}

Trauger, Sunia A. ^{[2
]}

Blain, Manon ^{[3
]}

Nadeau, Meghan ^{[1
]}

Patel, Bonny ^{[1
]}

Alvarez, Jorge I. ^{[4
]}

Mascanfroni, Ivan D. ^{[1
]}

Yeste, Ada ^{[1
]}

Kivisaekk, Pia ^{[1
]}

Kallas, Keith ^{[1
]}

Ellezam, Benjamin ^{[5
,6
]}

Bakshi, Rohit ^{[1
]}

Prat, Alexandre ^{[4
]}

Antel, Jack P. ^{[3
]}

Weiner, Howard L. ^{[1
]}

Quintana, Francisco J. ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA

[2] Harvard Univ, FAS Ctr Syst Biol, Boston, MA 02115 USA

[3] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Neuroimmunol Unit, Montreal, PQ H3A 2B4, Canada

[4] Univ Montreal, Dept Neurosci, Ctr Excellence Neur, Neuroimmunol Res Lab, Montreal, PQ, Canada

[5] Univ Montreal, Dept Pathol, Montreal, PQ H3C 3J7, Canada

[6] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

来源：

NATURE MEDICINE | 2014年 / 20卷 / 10期

基金：

美国国家卫生研究院;

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; REACTIVE ASTROCYTES; LACTOSYLCERAMIDE SYNTHASE; T-CELLS; EXPRESSION; MONOCYTES; MICE; INFILTRATION; ADHESION; DISTINCT;

D O I：

10.1038/nm.3681

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by beta-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.

引用

页码：1147 / 1156

页数：10

共 40 条

[1] Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool [J].

Ajami, Bahareh ;

Bennett, Jami L. ;

Krieger, Charles ;

McNagny, Kelly M. ;

Rossi, Fabio M. V. .

NATURE NEUROSCIENCE, 2011, 14 (09) :1142-U263

[2] Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis [J].

Basso, Alexandre S. ;

Frenkel, Dan ;

Quintana, Francisco J. ;

Costa-Pinto, Frederico A. ;

Petrovic-Stojkovic, Sanja ;

Puckett, Lindsay ;

Monsonego, Alon ;

Bar-Shir, Amnon ;

Engel, Yon ;

Gozin, Michael ;

Weiner, Howard L. .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (04) :1532-1543

[3] Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice [J].

Bush, TG ;

Puvanachandra, N ;

Horner, CH ;

Polito, A ;

Ostenfeld, T ;

Svendsen, CN ;

Mucke, L ;

Johnson, MH ;

Sofroniew, MV .

NEURON, 1999, 23 (02) :297-308

[4] Leukemia Inhibitory Factor Inhibits T Helper 17 Cell Differentiation and Confers Treatment Effects of Neural Progenitor Cell Therapy in Autoimmune Disease [J].

Cao, Wei ;

Yang, Yiqing ;

Wang, Zhengyi ;

Liu, Ailian ;

Fang, Lei ;

Wu, Fenglan ;

Hong, Jian ;

Shi, Yufang ;

Leung, Stewart ;

Dong, Chen ;

Zhang, Jingwu Z. .

IMMUNITY, 2011, 35 (02) :273-284

[5] Lactosylceramide Synthase as a Therapeutic Target to Mitigate Multiple Human Diseases in Animal Models [J].

Chatterjee, Subroto ;

Alsaeedi, Nezar .

BIOCHEMICAL ROLES OF EUKARYOTIC CELL SURFACE MACROMOLECULES, 2012, 749 :153-169

[6] Emerging roles of astrocytes in neural circuit development [J].

Clarke, Laura E. ;

Barres, Ben A. .

NATURE REVIEWS NEUROSCIENCE, 2013, 14 (05) :311-321

[7] Repertoire of microglial and macrophage responses after spinal cord injury [J].

David, Samuel ;

Kroner, Antje .

NATURE REVIEWS NEUROSCIENCE, 2011, 12 (07) :388-399

[8] Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE [J].

Farez, Mauricio F. ;

Quintana, Francisco J. ;

Gandhi, Roopali ;

Izquierdo, Guillermo ;

Lucas, Miguel ;

Weiner, Howard L. .

NATURE IMMUNOLOGY, 2009, 10 (09) :958-U44

[9] Lactosylceramide recruits PKCα/ε and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and adhesion to endothelial cells [J].

Gong, NL ;

Wei, HM ;

Chowdhury, SH ;

Chatterjee, S .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (17) :6490-6495

[10] Experimental autoimmune encephalomyelitis repressed by microglial paralysis [J].

Heppner, FL ;

Greter, M ;

Marino, D ;

Falsig, J ;

Raivich, G ;

Hövelmeyer, N ;

Waisman, A ;

Rülicke, T ;

Prinz, M ;

Priller, J ;

Becher, B ;

Aguzzi, A .

NATURE MEDICINE, 2005, 11 (02) :146-152

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