CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica

• DOI: 10.1186/s12974-019-1448-x
• Publication Date: 2019-03-09T07:02:36Z
• Authors: Lukmanee Tradtrantip; Tianjiao Duan; Michael R. Yeaman; Alan S. Verkman
• Keywords: Complement-dependent cytotoxicity; Messenger; Neurodegenerative; Mice; 0302 clinical medicine; 2.1 Biological and endogenous factors; Drug Interactions; Cell Line, Transformed; CD55 Antigens; Neuromyelitis Optica; Brain; Up-Regulation; 3. Good health; Spinal Cord; 5.1 Pharmaceuticals; Drug; CD55; Astrocyte; Biotechnology; Transcriptional Activation; Immunology; Clinical Sciences; 610; Cell Line; Dose-Response Relationship; 03 medical and health sciences; Rare Diseases; 616; Animals; Humans; RNA, Messenger; fas Receptor; RC346-429; Eye Disease and Disorders of Vision; Aquaporin 4; Neurology & Neurosurgery; Biomedical and Clinical Sciences; NMO; Dose-Response Relationship, Drug; Animal; Research; Neurosciences; Statins; Brain Disorders; Disease Models, Animal; Orphan Drug; Transformed; Astrocytes; Immunoglobulin G; Disease Models; RNA; Neurology. Diseases of the nervous system; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Aquaporin-4

Abstract Background Neuromyelitis optica spectrum disorder (herein called NMO) is an inflammatory demyelinating disease that can be initiated by binding of immunoglobulin G autoantibodies (AQP4-IgG) to aquaporin-4 on astrocytes, causing complement-dependent cytotoxicity (CDC) and downstream inflammation. The increased NMO pathology in rodents deficient in complement regulator protein CD59 following passive transfer of AQP4-IgG has suggested the potential therapeutic utility of increasing the expression of complement regulator proteins.

Methods A cell-based ELISA was developed to screen for pharmacological upregulators of endogenous CD55 and CD59 in a human astrocyte cell line. A statin identified from the screen was characterized in cell culture models and rodents for its action on complement regulator protein expression and its efficacy in models of seropositive NMO.

Results Screening of ~ 11,500 approved and investigational drugs and nutraceuticals identified transcriptional upregulators of CD55 but not of CD59. Several statins, including atorvastatin, simvastatin, lovastatin, and fluvastatin, increased CD55 protein expression in astrocytes, including primary cultures, by three- to four-fold at 24 h, conferring significant protection against AQP4-IgG-induced CDC. Mechanistic studies revealed that CD55 upregulation involves inhibition of the geranylgeranyl transferase pathway rather than inhibition of cholesterol biosynthesis. Oral atorvastatin at 10–20 mg/kg/day for 3 days strongly increased CD55 immunofluorescence in mouse brain and spinal cord and reduced NMO pathology following intracerebral AQP4-IgG injection.

Conclusion Atorvastatin or other statins may thus have therapeutic benefit in AQP4-IgG seropositive NMO by increasing CD55 expression, in addition to their previously described anti-inflammatory and immunomodulatory actions.