Alpha4beta1 integrin mediates the recruitment of immature dendritic cells across the blood-brain barrier during experimental autoimmune encephalomyelitis.
Dendritic cells (DCs) within the CNS are recognized to play an important role in the effector phase and propagation of the immune response in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. However, the mechanisms regulating DC trafficking into the CNS still need to be characterized. In this study, we show by performing intravital fluorescence videomicroscopy of the inflamed spinal cord white-matter microvasculature in SJL mice with EAE that immature, and to a lesser extent, LPS-matured, bone marrow-derived DCs efficiently interact with the CNS endothelium by rolling, capturing, and firm adhesion. Immature but not LPS-matured DCs efficiently migrated across the wall of inflamed parenchymal microvessels into the CNS. Blocking alpha4 integrins interfered with the adhesion but not the rolling or capturing of immature and LPS-matured DCs to the CNS microvascular endothelium, inhibiting their migration across the vascular wall. Functional absence of beta1 integrins but not of beta7 integrins or alpha4beta7 integrin similarly reduced the adhesion of immature DCs to the CNS microvascular endothelium, demonstrating that alpha4beta1 but not alpha4beta7 integrin mediates this step of immature DCs interaction with the inflamed blood-brain barrier during EAE. Our study shows that during EAE, especially immature DCs migrate into the CNS, where they may be crucial for the perpetuation of the CNS-targeted autoimmune response. Thus therapeutic targeting of alpha4 integrins affects DC trafficking into the CNS and may therefore lead to the resolution of the CNS autoimmune inflammation by reducing the number of CNS professional APCs.
Jain
Pooja
P
Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, PA 18902, USA. pjain@drexelmed.edu
Coisne
Caroline
C
Enzmann
Gaby
G
Rottapel
Robert
R
Engelhardt
Britta
B
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology
D039041:Integrin alpha4beta1