Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination.
Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.
Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.|Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA.|Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.|Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Eun Young
EY
Choi
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.
Jong-Hyung
JH
Lim
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.
Ales
A
Neuwirth
Clinic for Ophthalmology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Matina
M
Economopoulou
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.|Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Antonios
A
Chatzigeorgiou
Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.
Kyoung-Jin
KJ
Chung
Department for Neurology, University Münster, Germany.
Stefan
S
Bittner
Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
Seung-Hwan
SH
Lee
Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA.|Medizinische Klinik III, Eberhard Karls-University Tübingen, Tübingen, Germany.
Harald
H
Langer
Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Maryna
M
Samus
Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hyesoon
H
Kim
Department of Biomedical Sciences and Department of Pharmacology, Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
Geum-Sil
GS
Cho
Department of Neurology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Tjalf
T
Ziemssen
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Khalil
K
Bdeir
Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Frankfurt, Germany.
Emmanouil
E
Chavakis
Department of Neurology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jae-Young
JY
Koh
Bioceros, Utrecht, The Netherlands.
Louis
L
Boon
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Kavita
K
Hosur
Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Stefan R
SR
Bornstein
Department for Neurology, University Münster, Germany.
Sven G
SG
Meuth
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
George
G
Hajishengallis
Experimental Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland, USA.|Department of Clinical Pathobiochemistry, Faculty of Medicine, Technische Universität Dresden, Germany.|Department of Internal Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.|Center for Regenerative Therapies Dresden, Dresden, Germany.
Triantafyllos
T
Chavakis
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C491706:Edil3 protein, mouse; C491673:Il17ra protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D053722:Receptors, Interleukin-17