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Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
Tingjun Chen, … , Shihui Wei, Long-Jun Wu
Tingjun Chen, … , Shihui Wei, Long-Jun Wu
Published June 22, 2020
Citation Information: J Clin Invest. 2020;130(8):4025-4038. https://doi.org/10.1172/JCI134816.
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Research Article Autoimmunity Neuroscience Article has an altmetric score of 20

Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion

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Abstract

Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum–derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG dose dependent, AQP4 dependent, and, unexpectedly, microglia dependent. In vivo spinal cord imaging revealed a striking physical interaction between microglia and astrocytes that required signaling from astrocytes by the C3a fragment of their upregulated complement C3 protein. Astrocytes remained viable but lost AQP4. Previously unappreciated crosstalk between astrocytes and microglia involving early-activated CNS-intrinsic complement components and microglial C3a receptor signaling appears to be a critical driver of the precytolytic phase in the evolving NMO lesion, including initial motor impairment. Our results indicate that microglia merit consideration as a potential target for NMO therapeutic intervention.

Authors

Tingjun Chen, Vanda A. Lennon, Yong U. Liu, Dale B. Bosco, Yujiao Li, Min-Hee Yi, Jia Zhu, Shihui Wei, Long-Jun Wu

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Figure 6

Microglial ablation prevents motor impairment by NMO-IgG.

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Microglial ablation prevents motor impairment by NMO-IgG.
(A) Top: Timel...
(A) Top: Timeline of i.p. tamoxifen and diphtheria toxin (DT) administration and tissue harvesting for immunostaining. Bottom: Daily enumeration of microglial numbers (Iba1+) in the week following DT administration. n = 4 mice in each group (4 sections/mouse). (B) Representative serial images of Iba+ cells in cross sections of L4 cord. n = 4 mice in each group (4 sections/mouse). Scale bar: 200 μm. (C) Top: Timeline for intrathecal catheter placement, IgG infusion, and motor function evaluation in relation to microglial ablation (sequential tamoxifen and DT). Bottom: Rotarod testing documented that mice were spared motor impairment when microglia were reduced maximally at the time of NMO-IgG infusion. n = 4 mice in each group. (D) Representative images show astrocytic AQP4 and endothelial CD31 after NMO-IgG infusion with and without microglia ablation. n = 5 mice (4 sections/mouse). Scale bar: 20 μm. (E) Bar graph shows insignificant differences in relative length of parenchymal blood vessels (CD31+) covered by AQP4 (L4 level). n = 5 mice (4 sections/mouse). (F) NeuN staining and mask figures of NeuN+ cells at L4 level after NMO-IgG infusion, with or without microglia ablation. n = 5 mice (4 sections/mouse). Scale bar: 200 μm. (G) NeuN+ cell numbers at L4 spinal cord level shows sparing of neuronal marker immunoreactivity on day 5 of NMO-IgG infusion in mice undergoing microglial ablation. n = 5 mice (4 sections/mouse). Data presented as the mean ± SEM. ***P < 0.001; **P < 0.01; *P < 0.05 by 1-way ANOVA (A), 2-way ANOVA (C), or 2-tailed Student’s t test (day 5 in C, E, and G).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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