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

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.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...

Neuroinflammation in the central nervous system: Symphony of glial cells

“…The specific autoantibody of NMO has been identified as NMO-IgG recognizing aquaporin-4 (AQP4), a water channel clustered on the end feet of perivascular astrocytes (Lennon et al, 2004;Lennon, Kryzer, Pittock, Verkman, & Hinson, 2005). In in vitro experiments, the binding of IgG causes the coendocytosis of AQP4 and its coupled excitatory amino acid transporter 2 (EAAT2) in a complement independent manner, which subsequently causes the disruption of water and glutamate homeostasis and oligodendrocyte apoptosis (Hinson, Clift, Luo, Kryzer, & Lennon, 2017;Marignier et al, 2010;Nishiyama et al, 2016). The necrosis of astrocytes is caused by AQP4-IgG binding to AQP4, which induces complement-dependent cytotoxicity (CDC; Kinoshita et al, 2009;Sabater et al, 2009).…”

Second regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the immunomodulatory role of plasma exchange in central and peripheral nervous system disorders, Kuala Lumpur, Malaysia, 9th December 2017

“…Although TPE has been proven to be effective in patients with acute relapses of NMOSD, the role of TPE in RRMS is also gaining ground . Metha Apiwattanakul (MA), Consultant Neurologist from the Prasat Neurological Institute, Thailand summarized the complex, but ground breaking immunopathogenesis of NMOSD and multiple sclerosis (MS) . He explained in detail the role of pathogenic anti‐antibody Aquaporin 4 (AQP4)‐IgG binding in NMOSD and its effect on astrocytic death after gaining entry through the human blood brain barrier (BBB).…”

“…[14][15][16][17] Metha Apiwattanakul (MA), Consultant Neurologist from the Prasat Neurological Institute, Thailand summarized the complex, but ground breaking immunopathogenesis of NMOSD and multiple sclerosis (MS). [18][19][20] He explained in detail the role of pathogenic antiantibody Aquaporin 4 (AQP4)-IgG binding in NMOSD and its effect on astrocytic death after gaining entry through the human blood brain barrier (BBB). He also provided the encouraging high-quality trial data on the role of TPE in treating acute central nervous system inflammatory demyelinating diseases, particularly in patients with acute presentation NMOSD, Optic Neuritis and transverse myelitis.…”

Chansporter complexes in cell signaling

“…morphine was found to regulate expression of the complex via activation of protein kinase C, and it is suggested that the complex might play a role in morphine dependence [178]. In another recent study, the astrocytic Fc receptor was found to be required for autoantibody-induced internalization of AQP4 and EAAT2, a finding which may aid development of therapies to treat neuromyelitis optica, an autoimmune disease in which AQP4 autoantibodies cause CNS immunopathology and secondary CNS demyelination [179]. The findings of these two studies together with others described above underline the potential importance of chansporter complexes and their disruption to human disease processes.…”