EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells.
Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Florian
F
Wanke
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Sonja
S
Moos
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Andrew L
AL
Croxford
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
André P
AP
Heinen
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Stephanie
S
Gräf
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Bettina
B
Kalt
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Denise
D
Tischner
Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
Juan
J
Zhang
Analytical Sciences and Imaging, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
Isabelle
I
Christen
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Julia
J
Bruttger
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Nir
N
Yogev
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Yilang
Y
Tang
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Morad
M
Zayoud
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Nicole
N
Israel
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Khalad
K
Karram
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Sonja
S
Reißig
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Sonja M
SM
Lacher
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Christian
C
Reichhold
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Ilgiz A
IA
Mufazalov
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Avraham
A
Ben-Nun
Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
Tanja
T
Kuhlmann
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
Nina
N
Wettschureck
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
Andreas W
AW
Sailer
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
Klaus
K
Rajewsky
IFOM-The FIRC Institute of Molecular Oncology, 20139 Milan, Italy. Electronic address: stefano.casola@ifom.eu.
Stefano
S
Casola
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany. Electronic address: waisman@uni-mainz.de.
Ari
A
Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany. Electronic address: kurschus@uni-mainz.de.
Florian C
FC
Kurschus
D000818:Animals; D015551:Autoimmunity / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002490:Central Nervous System / Q000378:metabolism* / Q000502:physiology; D000072474:Cytochrome P450 Family 7 / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism / Q000502:physiology
C543809:Gpr183 protein, mouse; D053583:Interleukin-1beta; D053759:Interleukin-23; D043562:Receptors, G-Protein-Coupled; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse
7α,25-OHC; CH25H; CNS; EAE; EBI2; GPR183; Th17; microglia; multiple sclerosis; oxysterol