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 4

NMO-IgG induces microglial activation.

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NMO-IgG induces microglial activation. (A) Iba1+ microglia in representa...
(A) Iba1+ microglia in representative spinal cord images, longitudinal section (top, after 5 days of NMO-IgG), and L4 cross section (bottom, control-IgG and NMO-IgG). n = 5 mice (4 sections/mouse). Scale bars: 1 mm (top) and 200 μm (bottom). (B) Bar graphs compare, after 5 days of control-IgG or NMO-IgG infusion, intensity of Iba1+ staining: Iba+ cell numbers and Iba+ soma volumes. n = 5 mice (4 sections/mouse). (C) Representative images of microglia morphology (confocal, green; transformed skeletal, gray) in a control-IgG recipient (day 5), and 2 NMO-IgG recipients (days 3 and 5). n = 5 mice (4 sections/mouse). Scale bar: 20 μm. (D) Quantification of microglial process length (top) and branch number (bottom) on day 5 of control-IgG or on day 3 or day 5 of NMO-IgG infusion. n = 5 mice (4 sections/mouse). (E) Sholl analysis of microglia on day 5 of control-IgG or NMO-IgG infusion. n = 5 mice in each group (10 microglia/section, 4 sections/mouse). Data presented as the mean ± SEM. ***P < 0.001; *P < 0.05 by 2-tailed Student’s t test (B) or 1-way ANOVA (D).