title: Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions.
abstract: OBJECTIVE
  Blood-derived myeloid antigen-presenting cells (APCs) account for a significant proportion of the leukocytes found within lesions of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). These APCs along with activated microglia are thought to be pivotal in the initiation of the central nervous system (CNS)-targeted immune response in MS and EAE. However, the exact molecules that direct the migration of myeloid cells from the periphery across the blood-brain barrier (BBB) remain largely unknown.
  
  
  METHODS
  We identified Ninjurin-1 in a proteomic screen of human BBB endothelial cells (ECs). We assessed the expression of Ninjurin-1 by BBB-ECs and immune cells, and we determined the role of Ninjurin-1 in immune cell migration to the CNS in vivo in EAE mice.
  
  
  RESULTS
  Ninjurin-1 was found to be weakly expressed in the healthy human and mouse CNS but upregulated on BBB-ECs and on infiltrating APCs during the course of EAE and in active MS lesions. In human peripheral blood, Ninjurin-1 was predominantly expressed by monocytes, whereas it was barely detectable on T and B lymphocytes. Moreover, Ninjurin-1 neutralization specifically abrogated the adhesion and migration of human monocytes across BBB-ECs, without affecting lymphocyte recruitment. Finally, Ninjurin-1 blockade reduced clinical disease activity and histopathological indices of EAE and decreased infiltration of macrophages, dendritic cells, and APCs into the CNS.
  
  
  CONCLUSIONS
  Our study uncovers an important cell-specific role for Ninjurin-1 in the transmigration of inflammatory APCs across the BBB and further emphasizes the importance of myeloid cell recruitment during the development of neuroinflammatory lesions.
authors.affiliation: Neuroimmunology Research Unit, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Igal
authors.initials: I
authors.lastname: Ifergan
authors.forename: Hania
authors.initials: H
authors.lastname: Kebir
authors.forename: Simone
authors.initials: S
authors.lastname: Terouz
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Alvarez
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Lécuyer
authors.forename: Steve
authors.initials: S
authors.lastname: Gendron
authors.forename: Lyne
authors.initials: L
authors.lastname: Bourbonnière
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.forename: Alain
authors.initials: A
authors.lastname: Bouthillier
authors.forename: Robert
authors.initials: R
authors.lastname: Moumdjian
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.forename: Arsalan
authors.initials: A
authors.lastname: Haqqani
authors.forename: Armelle
authors.initials: A
authors.lastname: Klopstein
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Rubèn
authors.initials: R
authors.lastname: López-Vales
authors.forename: Thomas
authors.initials: T
authors.lastname: Birchler
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002490:Central Nervous System / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C484438:NINJ1 protein, human; D009414:Nerve Growth Factors