Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases

Aubé, Benoit; Lévesque, Sébastien A; Paré, Alexandre; Chamma, Émilie; Kébir, Hania; Gorina Mendiz, Roser; Lécuyer, Marc-André; Alvarez, Jorge I; De Koninck, Yves; Engelhardt, Britta; Prat, Alexandre; Côté, Daniel; Lacroix, Steve (2014). Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases. Journal of immunology, 193(5), pp. 2438-2454. American Association of Immunologists 10.4049/jimmunol.1400401

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Gorina Mendiz, Roser and Engelhardt, Britta

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0022-1767

Publisher:

American Association of Immunologists

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

07 Apr 2015 12:41

Last Modified:

11 May 2015 13:56

Publisher DOI:

10.4049/jimmunol.1400401

PubMed ID:

25049355

BORIS DOI:

10.7892/boris.66343

URI:

https://boris.unibe.ch/id/eprint/66343

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