Abstract
Autoantibodies against astrocyte water channel aquaporin-4 (AQP4) are thought to be pathogenic in neuromyelitis optica (NMO). Prior work has suggested that a key component of NMO autoantibody (NMO-IgG) pathogenesis is internalization of AQP4 and the associated glutamate transporter EAAT2, leading to glutamate excitotoxicity. Here, we show selective endocytosis of NMO-IgG and AQP4 in transfected cell cultures, but little internalization in brain in vivo. AQP4-dependent endocytosis of NMO-IgG occurred rapidly in various AQP4-transfected cell lines, with efficient transport from early endosomes to lysosomes. Cell surface AQP4 was also reduced following NMO-IgG exposure. However, little or no internalization of NMO-IgG, AQP4, or EAAT2 was found in primary astrocyte cultures, nor was glutamate uptake affected by NMO-IgG exposure. Following injection of NMO-IgG into mouse brain, NMO-IgG binding and AQP4 expression showed a perivascular astrocyte distribution, without detectable cellular internalization over 24 h. We conclude that astrocyte endocytosis of NMO-IgG, AQP4, and EAAT2 is not a significant consequence of AQP4 autoantibody in vivo, challenging generally accepted views about NMO pathogenesis.
Highlights
Binding of the neuromyelitis optica (NMO) autoantibody (NMO-IgG) to aquaporin-4 (AQP4) is pathogenic in NMO
NMO-IgG binding to AQP4 in transfected cell cultures caused internalization of itself and AQP4 by an endocytic mechanism, little or no internalization was found in astrocyte cultures or in brain
We found that NMO-IgG is internalized in several transfected cell lines expressing M1- or M23-AQP4
Summary
Binding of the neuromyelitis optica (NMO) autoantibody (NMO-IgG) to aquaporin-4 (AQP4) is pathogenic in NMO. Results: NMO-IgG binding does not cause endocytosis of itself, AQP4, or glutamate transporter EAAT2 in astrocyte cultures or in vivo. Little or no internalization of NMO-IgG, AQP4, or EAAT2 was found in primary astrocyte cultures, nor was glutamate uptake affected by NMO-IgG exposure. We conclude that astrocyte endocytosis of NMO-IgG, AQP4, and EAAT2 is not a significant consequence of AQP4 autoantibody in vivo, challenging generally accepted views about NMO pathogenesis. NMO lesions are produced in mice administered NMO-IgG and complement by intracerebral injection [7], in rats with preexisting neuroinflammation administered NMO-IgG (8 –10), and in spinal cord slice cultures exposed to NMO-IgG and complement [11] It is not known how NMO-IgG enters the central nervous system through an initially intact blood-brain barrier or why NMOIgG does not cause pathology in peripheral tissues where AQP4 is expressed. Our results challenge a widely cited view of NMO disease pathogenesis
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