Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
Tingjun Chen, Vanda A. Lennon, Yong U. Liu, Dale B. Bosco, Yujiao Li, Min-Hee Yi, Jia Zhu, Shihui Wei, Long-Jun Wu
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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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 7

NMO-IgG induces astrocyte-microglia interaction.

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NMO-IgG induces astrocyte-microglia interaction. (A) Interaction between...
(A) Interaction between Iba1+ microglia (green) and GFAP+ astrocytes (red) is inferred from enlargement and overlapping (shown by arrow heads) of those cells and their processes in dual immunostained L4 spinal cord of NMO-IgG–recipient mice compared with control-IgG recipients. n = 5 mice (4 sections/mouse). Scale bars: 200 μm (left) and 20 μm (right). (B) Venn diagram and (C) bar graph quantifies (by ImageJ software) the increase in overlap from 17% (control-IgG recipients) to 65% (NMO-IgG recipients). n = 5 mice (4 sections/mouse). (D) Representative 2-photon images captured in vivo show, at baseline time (top, before NMO-IgG infusion), few processes extending from microglia (green, Cx3cr1gfp/+; astrocytes are labeled red by SR101). After NMO-IgG infusion (bottom), microglial processes converged toward an astrocyte. Arrowheads indicate the converging microglial processes. n = 3 mice. Scale bars: 20 μm. (E) Graph shows quantified Cx3cr1gfp/+ intensity of microglial processes in the area surrounding the SR101-labeled astrocyte (yellow circles in D). n = 3 mice. (F) Bar graph shows the microglial convergence event frequency (convergence events per 10 minutes) after NMO-IgG or control-IgG infusion (for 30 minutes). n = 3 mice. Data presented as the mean ± SEM. ***P < 0.001 by 2-tailed Student’s t test (C, E, and F).