Role of ninjurin‐1 in the migration of myeloid cells to central nervous system inflammatory lesions

I Ifergan, H Kebir, S Terouz, JI Alvarez… - Annals of …, 2011 - Wiley Online Library
I Ifergan, H Kebir, S Terouz, JI Alvarez, MA Lécuyer, S Gendron, L Bourbonnière, IR Dunay
Annals of neurology, 2011Wiley Online Library
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 …
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.
Interpretation
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.ANN NEUROL 2011
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