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 1

NMO-IgG intrathecal infusion induces motor impairment.

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NMO-IgG intrathecal infusion induces motor impairment. (A) Timeline for ...
(A) Timeline for surgery, intrathecal infusions, and motor function testing. (B) Rotarod tests show dose-dependent motor impairment (measured as fall latency) with infusion of NMO-IgG (n = 5 for each group), but not control-IgG (n = 4). (C) Gait illustrated by representative paw print images before and after NMO-IgG or control-IgG infusion. (D) Stride length of NMO-IgG recipients (n = 5 for each group) is shorter than that of control-IgG recipients (n = 4), indicating significant gait impairment. (E) Immunofluorescence staining confirms AQP4 protein expression in the spinal cord of representative WT mouse (top right) and its absence in AQP4null mouse (bottom right). n = 5 mice (4 sections/mouse). Scale bars: 200 μm (left) and 20 μm (right). (F) Rotarod analysis shows NMO-IgG infusion fails to induce motor impairment in AQP4null mice (n = 5 in NMO-IgG group; n = 4 in control-IgG group). Lack of performance improvement in both AQP4null groups concurs with reported AQP4 involvement in learning (24). (G) In WT mice, infusion of AQP4-specific monoclonal mouse IgG induced the same motor impairment phenotype as NMO-IgG (n = 5 in AQP4-IgG group; n = 4 in control-IgG group). (H) In AQP4null mice, AQP4-specific monoclonal mouse IgG did not impair motor function (n = 5 for each group). Data presented as the mean ± SEM. ***P < 0.001 by 2-way ANOVA (B, D, and F–H).