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 Article has an altmetric score of 20

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 8

Complement signaling drives astrocyte-microglia interaction.

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Complement signaling drives astrocyte-microglia interaction. (A) Dual st...
(A) Dual staining reveals immunoreactivities for complement C3 (green) and GFAP (red, astrocytes) in L4 spinal cord of representative IgG-recipient mice on day 5 of IgG infusion. C3 is restricted to blood vessel lumen in control-IgG recipient but is expressed robustly in enlarged astrocytes (arrowheads) of NMO-IgG recipient. n = 5 mice (4 sections/mouse). Scale bar: 20 μm. (B) Bar graph quantifies C3+ astrocytes in both IgG recipient groups. n = 5 mice (4 sections/mouse). (C) Complement C3a receptor immunoreactivity (red) is restricted to Iba1+ microglia (green) in spinal cords of both groups of mice, but is greatly upregulated in NMO-IgG recipients (dual immunostaining, day 5 of IgG infusion). n = 5 mice (4 sections/mouse). Scale bar: 20 μm. (D) In ex vivo time-lapse imaging of brain slice from naive Cx3cr1gfp/+ mouse, processes of microglia converge toward pipette tip (red) containing recombinant C3a, by comparison with pipette containing artificial CSF (aCSF). n = 3 mice for each group. Scale bar: 20 μm. (E) Quantified data show the change in microglial process Cx3cr1gfp/+ intensity in the area surrounding the tip (dotted circles in D) in response to C3a. n = 3 mice in each group. Data presented as the mean ± SEM. ***P < 0.001 by 2-tailed Student’s t test (B) or 2-way ANOVA (E).