ASK1 Inhibition Ameliorates Optic Neuritis by Modulating Glial Innate Immunity

1. Xiaoli Guo¹
2. Chikako Harada¹
3. Kazuhiko Namekata¹
4. Atsuko Kimura¹
5. Hidenori Ichijo²
6. Takayuki Harada¹

¹Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
²Laboratory of Cell Signaling, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan

Purpose: To elucidate a potential role of ASK1 on glial innate immunity during optic neuritis in multiple sclerosis (MS).

Methods: ASK1-deficient mice were used for the induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Clinical scoring, visual function measurement, histopathology analysis and quantitative real-time PCR analysis of several key chemokines and Toll-like receptors (TLRs) were performed on EAE and normal mice. For in vitro assays, primary cultured astrocytes and microglia were prepared and used. A specific small molecular weight inhibitor of ASK1, referred to as MSC2032964A was identified by a high-throughput screening followed by medicinal chemistry optimization. The effects of this compound on EAE were evaluated.

Results & Conclusions: ASK1 deficiency ameliorated the severity of EAE in both optic nerves and spinal cords, which was accompanied by histopathologically reduced neuroinflammation. However, ASK1 deficiency had no effect on the proliferation capability of T cells. Moreover, expression of TLRs in activated astrocytes and microglia was upregulated during EAE, and we found that TLRs can synergize with ASK1-p38 MAPK signaling in the release of key chemokines from astrocytes. Furthermore, oral treatment with the ASK1 inhibitor MSC2032964A suppressed EAE-induced autoimmune inflammation in both optic nerves and spinal cords. These findings suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for optic neuritis in MS.