title: Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues.
abstract: Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis.
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Youngpyo
authors.initials: Y
authors.lastname: Nam
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Jong-Heon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Minchul
authors.initials: M
authors.lastname: Seo
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Myungwon
authors.initials: M
authors.lastname: Jin
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Jeon
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Jung-wan
authors.initials: JW
authors.lastname: Seo
authors.affiliation: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Won-Ha
authors.initials: WH
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine and Applied Radiological Institute, Jeju National University, Jeju 690-756, Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Bing
authors.affiliation: College of Veterinary Medicine and Applied Radiological Institute, Jeju National University, Jeju 690-756, Korea.
authors.forename: Youngheun
authors.initials: Y
authors.lastname: Jee
authors.affiliation: Center of Biostatistics, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
authors.forename: Won Kee
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Kyungpook National University School of Medicine, Daegu 700-422, Korea, and.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 501-746, Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.affiliation: From the Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 700-422, Korea, ksuk@knu.ac.kr.
authors.forename: Kyoungho
authors.initials: K
authors.lastname: Suk
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D017353:Gene Deletion; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D007371:Interferon-gamma; D020381:Interleukin-17; D000071068:Lipocalin-2; D054834:Lipocalins; D020780:Matrix Metalloproteinase 9; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; C508313:Slc22a17 protein, mouse; C098680:Il17a protein, mouse; C539901:Rorc protein, mouse; C071332:Lcn2 protein, mouse; C501830:Mmp9 protein, mouse
keywords: Astrocyte; Autoimmune Disease; Central Nervous System; EAE; LCN2; Microglia; Multiple Sclerosis; Neuroinflammation