Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration
Anne Winkler, … , Stefan Nessler, Christine Stadelmann
Anne Winkler, … , Stefan Nessler, Christine Stadelmann
Published March 1, 2021
Citation Information: J Clin Invest. 2021;131(5):e141694. https://doi.org/10.1172/JCI141694.
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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 4

Depletion of PMNs prevents BBB disruption and astrocyte lesion formation 6 hours after lesion induction.

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Depletion of PMNs prevents BBB disruption and astrocyte lesion formation...
The mAb RP-3 was injected i.p. 18 hours prior to and at the time of lesion induction, and animals were perfused 6 hours later. Treatment of rats with RP-3 specifically decreased blood PMN numbers to 10% compared with control Ab–injected animals, which is reflected by a significant reduction in PMN numbers in the brain parenchyma 6 hours after lesion induction (A). PMNs are shown as pink using CAE stain; number of lesions: n = 6. Depletion of PMNs resulted in a significant reduction in FITC-albumin extravasation (B). Number of lesions: control, n = 4; RP-3, n = 6. Astrocyte lesion formation (C, dotted lines indicate area of GFAP loss, higher magnification of insets shown in a and b; number of lesions n = 6). Mann-Whitney U test. **P < 0.01. Data are shown as mean ± SEM. Scale bars: 100 μm (A); 500 μm (B and C); 20 μm (a and b).