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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Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion

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 2

NMO-IgG induces AQP4 loss in spinal cord.

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NMO-IgG induces AQP4 loss in spinal cord. (A) Representative staining im...
(A) Representative staining images show longitudinal sections: AQP4 (top) and DAPI (bottom) in NMO-IgG–recipient mice after 5 days of IgG infusion. n = 5 mice (4 sections/mouse). Scale bar: 1 mm. (B) Representative Western blot images of AQP4 expression in corresponding spinal cord lysates. n = 3 mice. (C) Bar graph shows comparative Western blot quantification of AQP4 protein level (n = 3 mice). (D) L4 cross sections: astrocytic AQP4 (green) and endothelial CD31 (red) after control-IgG or NMO-IgG. n = 5 mice (4 sections/mouse). Scale bar: 20 μm. (E) Bar graph depicts relative length of parenchymal blood vessel (CD31+) covered by AQP4 (L4 level). n = 5 mice (4 sections/mouse). Data presented as the mean ± SEM. ***P < 0.001 by 2-tailed Student’s t test (C and E).