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

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 3

NMO-IgG induces astrocyte activation and neuronal injury.

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NMO-IgG induces astrocyte activation and neuronal injury. (A) GFAP immun...
(A) GFAP immunoreactivity after NMO-IgG (top, longitudinal section; bottom right, L4 cross section) or control-IgG (bottom left, L4 cross section); insets are higher magnifications of areas boxed in ventral horns. n = 5 mice (4 sections/mouse). Scale bars: 1 mm (top), 200 μm (bottom), and 20 μm (insets). (B) Numbers of astrocytes (GFAP+) and astrocyte cell body volume after 5 days of infusion with control-IgG or NMO-IgG. n = 5 mice (4 sections/mouse). (C) NeuN staining and mask figures of NeuN+ cell shapes at L4 cross section after NMO-IgG or control-IgG infusion. n = 5 mice (4 sections/mouse). Scale bars: 200 μm. (D) NeuN+ cell counts at L4 spinal cord after 5 days of NMO-IgG or control-IgG infusion. n = 5 mice (4 sections/mouse). Data presented as the mean ± SEM. ***P < 0.001 by 2-tailed Student’s t test (B and D).