Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration
Anne Winkler, Claudia Wrzos, Michael Haberl, Marie-Theres Weil, Ming Gao, Wiebke Möbius, Francesca Odoardi, Dietmar R. Thal, Mayland Chang, Ghislain Opdenakker, Jeffrey L. Bennett, Stefan Nessler, Christine Stadelmann
Anne Winkler, Claudia Wrzos, Michael Haberl, Marie-Theres Weil, Ming Gao, Wiebke Möbius, Francesca Odoardi, Dietmar R. Thal, Mayland Chang, Ghislain Opdenakker, Jeffrey L. Bennett, Stefan Nessler, Christine Stadelmann
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Research Article Neuroscience

Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration

Abstract

Approximately 80% of neuromyelitis optica spectrum disorder (NMOSD) patients harbor serum anti–aquaporin-4 autoantibodies targeting astrocytes in the CNS. Crucial for NMOSD lesion initiation is disruption of the blood-brain barrier (BBB), which allows the entrance of Abs and serum complement into the CNS and which is a target for new NMOSD therapies. Astrocytes have important functions in BBB maintenance; however, the influence of their loss and the role of immune cell infiltration on BBB permeability in NMOSD have not yet been investigated. Using an experimental model of targeted NMOSD lesions in rats, we demonstrate that astrocyte destruction coincides with a transient disruption of the BBB and a selective loss of occludin from tight junctions. It is noteworthy that BBB integrity is reestablished before astrocytes repopulate. Rather than persistent astrocyte loss, polymorphonuclear leukocytes (PMNs) are the main mediators of BBB disruption, and their depletion preserves BBB integrity and prevents astrocyte loss. Inhibition of PMN chemoattraction, activation, and proteolytic function reduces lesion size. In summary, our data support a crucial role for PMNs in BBB disruption and NMOSD lesion development, rendering their recruitment and activation promising therapeutic targets.

Authors

Anne Winkler, Claudia Wrzos, Michael Haberl, Marie-Theres Weil, Ming Gao, Wiebke Möbius, Francesca Odoardi, Dietmar R. Thal, Mayland Chang, Ghislain Opdenakker, Jeffrey L. Bennett, Stefan Nessler, Christine Stadelmann

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Figure 6

Resealing of the BBB to fibrinogen and tight junctions in human NMOSD lesions.

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Resealing of the BBB to fibrinogen and tight junctions in human NMOSD le...
In lesion areas of ongoing and recent astrocyte destruction, perivascular fibrinogen leakage is observed (biopsy, patient 3) (A). No fibrinogen leakage from blood vessels is observed in later-stage human NMOSD lesions with established astrocyte loss (biopsy, patient 1) (B). A resealed BBB was also observed in autopsies with later stage NMOSD lesions (C). Here, claudin-5 expression was present in blood vessels visualized using the basal lamina marker collagen IV (D) (serial section of lesion displayed in C, patient 9). Quantification of the percentage of claudin-5–positive blood vessels is shown (E). Additionally, endothelial cells expressed occludin and claudin-3 at their tight junctions in healthy brain tissue as well as in NMOSD lesions (F). Blood vessels are visualized using the basal lamina marker LAMγ1 (patient 7). TJ form electron-dense structures at the intercellular cleft (endothelium, blue; monocyte, red; patient 7). (G). (A–C) Dotted lines delineate lesion border. Asterisks mark bleeding from surgery. Arrowheads indicates big blood vessel. (E) Number of patients: controls, n = 5; NMOSD, n = 4. At least 117 blood vessels were evaluated per case. Kruskal-Wallis test followed by Dunn’s multiple comparison test revealed no significant differences in the percentage of claudin-5–positive blood vessels between groups. Data are shown as mean ± SEM. Scale bars: 500 μm (A, B, and C); 20 μm (D); 50 μm (F); 5 μm (G); 500 nm (G, a and b).