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Aquaporin-4 Removal from the Plasma Membrane of Human Müller Cells by AQP4-IgG from Patients with Neuromyelitis Optica Induces Changes in Cell Volume Homeostasis: the First Step of Retinal Injury?

Molecular Neurobiology volume 58, pages 5178–5193 (2021)Cite this article

Abstract

Aquaporin-4 (AQP4) is the target of the specific immunoglobulin G autoantibody (AQP4-IgG) produced in patients with neuromyelitis optica spectrum disorders (NMOSD). Previous studies demonstrated that AQP4-IgG binding to astrocytic AQP4 leads to cell-destructive lesions. However, the early physiopathological events in Müller cells in the retina are poorly understood. Here, we investigated the consequences of AQP4-IgG binding to AQP4 of Müller cells, previous to the inflammatory response, on two of AQP4’s key functions, cell volume regulation response (RVD) and cell proliferation, a process closely associated with changes in cell volume. Experiments were performed in a human retinal Müller cell line (MIO-M1) exposed to complement-inactivated sera from healthy volunteers or AQP4-IgG positive NMOSD patients. We evaluated AQP4 expression (immunofluorescence and western blot), water permeability coefficient, RVD, intracellular calcium levels and membrane potential changes during hypotonic shock (fluorescence videomicroscopy) and cell proliferation (cell count and BrdU incorporation). Our results showed that AQP4-IgG binding to AQP4 induces its partial internalization, leading to the decrease of the plasma membrane water permeability, a reduction of swelling-induced increase of intracellular calcium levels and the impairment of RVD in Müller cells. The loss of AQP4 from the plasma membrane induced by AQP4-IgG positive sera delayed Müller cells’ proliferation rate. We propose that Müller cell dysfunction after AQP4 removal from the plasma membrane by AQP4-IgG binding could be a non-inflammatory mechanism of retinal injury in vivo, altering cell volume homeostasis and cell proliferation and consequently, contributing to the physiopathology of NMOSD.

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Data Availability

The datasets generated and/or analyzed during the current study are available upon reasonable request.

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Acknowledgements

The authors thank Dr. Astrid Limb (University College London, London, UK) for providing the human Müller Cell Line (MIO-M1) and Natalia Beltramone, Germán La Iacona, and Ricardo Dorr for technical assistance.

Funding

This study was supported by grants from the University of Buenos Aires (UBA-SECYT, 20020130100682BA, 2018–2021, Argentina) to Claudia Capurro; the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT 2019–01707, Argentina) to Claudia Capurro and the Spanish Ministry of Economy and Competitiveness, co-financed by the Carlos III Health Institute (ISCIII) and European Regional Development Fund (FEDER, PI16/00493) to Miriam Echevarría.

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Authors and Affiliations

  1. Departamento de Ciencias Fisiológicas, Laboratorio de Biomembranas, Facultad de Medicina, Instituto de Fisiología y Biofísica “Bernardo Houssay” (IFIBIO‐HOUSSAY), Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina

    Vanina Netti, Juan Fernández, Gisela Di Giusto, Paula Ford & Claudia Capurro

  2. Servicio de Neurología, Centro Universitario de Neurología Dr. J.M. Ramos Mejía, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Luciana Melamud

  3. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Seville, Spain

    Pablo Garcia-Miranda & Miriam Echevarría

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  1. Vanina Netti
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  2. Juan Fernández
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Contributions

Claudia Capurro and Vanina Netti designed the study, interpreted the data, and coordinated the project. Vanina Netti and Juan Fernández conducted the experiments, data collection, and statistical analysis. Luciana Melamud provided consultation for clinical relevance. Pablo García-Miranda and Gisela Di Giusto provided consultation for methodology and conducted some experiments. Paula Ford and Miriam Echevarria contributed to the disign stages and interpretation of the research. The manuscript was written by Claudia Capurro and Vanina Netti and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Claudia Capurro.

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Ethics Approval

The study was approved by the Institutional Ethics Committee for Research in Translational Medicine Alberto C. Taquini of the School of Medicine, University of Buenos Aires (IATIMET, N°: PICT2019/10707 version 1.0), which is in compliance with the International Guideline for Human Research protection as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Netti, V., Fernández, J., Melamud, L. et al. Aquaporin-4 Removal from the Plasma Membrane of Human Müller Cells by AQP4-IgG from Patients with Neuromyelitis Optica Induces Changes in Cell Volume Homeostasis: the First Step of Retinal Injury?. Mol Neurobiol 58, 5178–5193 (2021). https://doi.org/10.1007/s12035-021-02491-x

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Keywords

  • Aquaporin 4
  • AQP4-IgG
  • Human Müller cells
  • Cell volume regulation
  • Cell proliferation