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

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.

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

“…Our understanding of the role of complement regulators represents a great research opportunity. Recently, among various other statins, atorvastatin upregulated CD55 and reduced pathology in an experimental mouse model . The site at which the therapy induces the upregulation of complement regulatory proteins in seropositive patients with NMOSD warrants further investigation.…”

“…Additionally, the discovery of the requirement for complement in the formation of lesions suggests that complement inhibitors, such as the C1 inhibitor, may be an effective approach to limit CNS injury in patients with NMO. Similarly, the upregulation of complement regulators, such as CD55, by statins may provide a substantial clinical benefit . The therapeutic monoclonal IgG eculizumab that neutralizes the complement protein C5 appears to be well tolerated, reduces the frequency of attack and improves neurological disability when used to treat intractable cases .…”

Complement Activation in Association with Markers of Neutrophil Extracellular Traps and Acute Myocardial Infarction in Stable Coronary Artery Disease

“…Lastly, all included patients were treated with aspirin for at least a week before Mediators of Inflammation inclusion and nearly all used statins. Aspirin has been shown to inhibit complement activation and NET formation [50][51][52], and statin use has been shown to both stimulate and inhibit NET formation [53][54][55][56]; thus, this medication may have influenced the observed associations in our cohort.…”

Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

“…The results also implicate complement regulator proteins as new targets in NMO in which their upregulation is predicted to protect against complement‐induced injury. Motivated by these observations, drug screening identified statins as transcriptional enhancers of CD55 expression in astrocyte cell culture models and in mice, and reported that oral atorvastatin significantly reduced NMO pathology in a passive transfer mouse model of NMO .…”

“…These data offered proof‐of‐concept for the potential utility of a remyelinating approach in NMO. Animal models of NMO have also been used to demonstrate efficacy of C1q‐targeted and Fc hexamer complement therapeutics, aquaporumab antibody and small molecule blockers of AQP4‐IgG/AQP4 binding, IgG‐inactivating enzymes , IVIG and a statin upregulator of CD55 , as well as the lack of efficacy of various proposed therapeutics including C1‐esterase inhibitor .…”