Angiotensin AT2-receptor induced interleukin-10 attenuates neuromyelitis optica spectrum disorder-like pathology

Reza M. H. Khorooshi, Emil Ulrikkaholm Tofte-Hansen, Camilla Tygesen, Roser Montañana-Rosell, Hannah Liska Limburg, Joanna Marczynska, Nasrin Asgari, Muscha Steckelings, Trevor Owens*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory central nervous system (CNS) disease for which there is no cure. Immunoglobulin G autoantibodies specific for the water channel aquaporin-4 are a serum biomarker, believed to induce complement-dependent astrocyte damage with secondary demyelination. Objective: To investigate the effect of angiotensin AT2 receptor (AT2R) stimulation on NMOSD-like pathology and its underlying mechanism. Methods: NMOSD-like pathology was induced in mice by intracerebral injection of immunoglobulin-G isolated from NMOSD patient serum, with complement. This mouse model produces the characteristic histological features of NMOSD. A specific AT2R agonist, Compound 21 (C21), was given intracerebrally at day 0 and by intrathecal injection at day 2. Results: Loss of aquaporin-4 and glial fibrillary acidic protein was attenuated by treatment with C21. Administration of C21 induced mRNA for interleukin-10 in the brain. NMOSD-like pathology was exacerbated in interleukin-10-deficient mice, suggesting a protective role. C21 treatment did not attenuate NMOSD-like pathology in interleukin-10-deficient mice, indicating that the protective effect of AT2R stimulation was dependent on interleukin-10. Conclusion: Our findings identify AT2R as a novel potential therapeutic target for the treatment of NMOSD. Interleukin-10 signaling is an essential part of the protective mechanism counteracting NMOSD pathology.

Original languageEnglish
JournalMultiple Sclerosis Journal
Volume26
Issue number10
Pages (from-to)1187-1196
ISSN1352-4585
DOIs
Publication statusPublished - 1. Sep 2020

Keywords

  • Compound 21
  • IL-10
  • Neuromyelitis optica spectrum disorder
  • angiotensin AT2 receptor
  • astrocytopathology

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