title: Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases.
abstract: Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.
authors: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de l'Université Laval, Quebec, Quebec G1V 4G2, Canada; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Quebec, Quebec G1V 0A6, Canada; Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Université Laval, Quebec, Quebec G1J 2G3, Canada; Centre d'Optique, Photonique et Laser, Université Laval, Quebec, Quebec G1V 0A6, Canada;
authors: Benoit
authors: B
authors: Aubé
authors: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de l'Université Laval, Quebec, Quebec G1V 4G2, Canada; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Quebec, Quebec G1V 0A6, Canada;
authors: Sébastien A
authors: SA
authors: Lévesque
authors: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de l'Université Laval, Quebec, Quebec G1V 4G2, Canada; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Quebec, Quebec G1V 0A6, Canada;
authors: Alexandre
authors: A
authors: Paré
authors: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Université Laval, Quebec, Quebec G1J 2G3, Canada; Centre d'Optique, Photonique et Laser, Université Laval, Quebec, Quebec G1V 0A6, Canada;
authors: Émilie
authors: É
authors: Chamma
authors: Unité de Neuroimmunologie, Centre d'Excellence en Neuromique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada; and.
authors: Hania
authors: H
authors: Kébir
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors: Roser
authors: R
authors: Gorina
authors: Unité de Neuroimmunologie, Centre d'Excellence en Neuromique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada; and.
authors: Marc-André
authors: MA
authors: Lécuyer
authors: Unité de Neuroimmunologie, Centre d'Excellence en Neuromique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada; and.
authors: Jorge I
authors: JI
authors: Alvarez
authors: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Université Laval, Quebec, Quebec G1J 2G3, Canada;
authors: Yves
authors: Y
authors: De Koninck
authors: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors: Britta
authors: B
authors: Engelhardt
authors: Unité de Neuroimmunologie, Centre d'Excellence en Neuromique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Quebec H3C 3J7, Canada; and.
authors: Alexandre
authors: A
authors: Prat
authors: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Université Laval, Quebec, Quebec G1J 2G3, Canada; Centre d'Optique, Photonique et Laser, Université Laval, Quebec, Quebec G1V 0A6, Canada;
authors: Daniel
authors: D
authors: Côté
authors: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de l'Université Laval, Quebec, Quebec G1V 4G2, Canada; Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Quebec, Quebec G1V 0A6, Canada; Steve.Lacroix@crchul.ulaval.ca.
authors: Steve
authors: http://orcid.org/0000-0003-0781-6371
authors: S
authors: Lacroix
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009471:Neuromyelitis Optica / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology