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Xiaoli Guo, Kazuhiko Namekata, Chikako Harada, Takayuki Harada; Combined inhibition of angiotensin II type 1 receptor and ASK1 significantly attenuates autoimmune optic neuritis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5769. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To study the effects of combined inhibition of angiotensin II type 1 receptor (AT1R) and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase (MAP3K), on optic neuritis in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
We induced EAE in female wild-type and ASK1-deficient mice. The effects of angiotensin II (AngII), the principal effector molecule of the renin-angiotensin system (RAS), and Toll-like receptor (TLR) signaling on EAE were examined. Clinical signs were scored daily and visual function was assessed by multifocal electroretinograms. Histopathological analysis of spinal cords and optic nerves was performed. Primary cultured astrocytes and bone marrow-derived dendritic cells (DC) were used to elucidate the relationship between AngII and TLR expression.
We demonstrated that AngII expression is increased in the early phase of EAE and AngII induces TLR4 expression via an NF-κB pathway in astrocytes and DCs. Since we previously demonstrated that ASK1 binds to TLR4 and regulates innate immune responses, we examined possible interactions between the RAS and ASK1 signaling. Combined application of an AT1R antagonist, NF-κB nuclear translocation inhibitor and ASK1 inhibitor suppressed chemokine productions in astrocytes and DCs, reduced antigen-presentation capability of DCs and T cell proliferation. Consistent with these findings, in vivo administration of an AT1R antagonist to ASK1-deficient mice significantly reduced the incidence of EAE, and attenuated demyelination in spinal cords and optic nerves, retinal ganglion cell death and visual impairment.
Our findings suggest a novel pathway of RAS-NF-κB-TLR4-ASK1 in neural and immune cells as a valid therapeutic target for optic neuritis. Prescribed drugs to treat high blood pressure may be available for the prevention and treatment for neuroinflammatory diseases.
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