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Microglia complement astrocytes in neuromyelitis optica
Zahra Moinfar, Scott S. Zamvil
Zahra Moinfar, Scott S. Zamvil
Published June 22, 2020
Citation Information: J Clin Invest. 2020;130(8):3961-3964. https://doi.org/10.1172/JCI138804.
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Commentary

Microglia complement astrocytes in neuromyelitis optica

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Abstract

Neuromyelitis optica (NMO) is a central nervous system (CNS) inflammatory autoimmune disease caused by antibodies against aquaporin-4 (AQP4) expressed on astrocytes. Binding of AQP4-specific antibodies (NMO-IgG) triggers activation of the complement cascade, which is responsible for astrocyte loss and secondary demyelination. Although the role for the cytolytic complement proteins in astrocyte destruction in NMO is well established, little is known regarding the initial phase of astrocyte injury. In this issue of the JCI, Chen and colleagues evaluated the precytolytic phase when NMO-IgG binds astrocytes in vivo in the absence of exogenous complement. NMO-IgG alone caused astrocyte activation and AQP4 loss. Surprisingly, microglia, CNS-resident innate immune cells that produce endogenous complement, were required for clinical manifestations of disease, a finding that suggests microglia may serve as a therapeutic target in NMO.

Authors

Zahra Moinfar, Scott S. Zamvil

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Figure 1

Astrocytes cooperate with microglia in complement-mediated CNS damage in NMO.

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Astrocytes cooperate with microglia in complement-mediated CNS damage in...
(A) A model for astrocyte-microglia interaction in precytolytic tissue injury in NMO. (i) AQP4-specific IgG1 is produced in secondary lymphoid tissue outside the CNS. AQP4-specific antibodies bind to AQP4 on astrocytic endfoot processes, leading to AQP4 internalization, reduced cell surface AQP4 expression, and astrocytic activation. (ii) Activated astrocytes produce elevated C3 that is cleaved to C3a and C3b. (iii) Secreted C3a binds C3aR on resting microglia, promoting microglial activation, production of C1q, and convergence toward astrocytes. (iv) C1q promotes localized injury to neurons and oligodendrocytes. (B) Activation of the classical complement cascade leads to sustained CNS tissue damage in NMO. (i) C1q binds the framework constant (Fc) region of adjacent AQP4 antibodies bound to AQP4 in close proximity, attracting C1r and C1s. (ii) This C1 complex activates C4 and C2 components that lead to formation of C3 convertase, producing C3b, which together with C4b and C2b create the C5 convertase. Eculizumab (Soliris), a C5-convertase inhibitor, is approved for treatment of NMO. (iii) C5b, one of the 2 C5 cleavage products, together with C6–C9 proteins form the membrane attack complex (MAC), which leads to astrocyte lysis and tissue necrosis. This figure was adapted with permission from Kenneth Probst (Xavier Studio).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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