Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Shannon R. Hinson, Ian C. Clift, Ningling Luo, Thomas J. Kryzer, Vanda A Lennon

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

Original languageEnglish (US)
Pages (from-to)5491-5496
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number21
DOIs
StatePublished - May 23 2017

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Excitatory Amino Acid Transporter 2
Aquaporin 4
Amino Acid Transport System X-AG
Aquaporins
Fc Receptors
Autoantibodies
Central Nervous System
Immunoglobulin G
Neuromyelitis Optica
Demyelinating Diseases
Interleukin-6
Complement Activation
Endocytosis
Multiple Sclerosis
Glutamic Acid
Edema
Membrane Proteins
Homeostasis

Keywords

  • Autoimmune astrocytopathy
  • CD32
  • CD64
  • Neuromyelitis optica
  • Pathogenic IgG

ASJC Scopus subject areas

  • General

Cite this

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor. / Hinson, Shannon R.; Clift, Ian C.; Luo, Ningling; Kryzer, Thomas J.; Lennon, Vanda A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 21, 23.05.2017, p. 5491-5496.

Research output: Contribution to journalArticle

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