br ASK in multiple sclerosis and optic neuritis

ASK1 in multiple sclerosis and optic neuritis Multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), is the most common neurological disease among young adults in the United States and Europe (Dutta and Trapp, 2011). Although MS primarily affects myelin, axonal degeneration and neuron loss frequently occur early in the course of the disease. While the functional consequences of inflammation and demyelination are at least in part reversible, the deficit due to axonal loss is irreversible, leading to permanent disability (Bjartmar et al., 2000, Bjartmar et al., 2003, Kornek and Lassmann, 1999). Therapeutic strategies to prevent axonal and neuronal degeneration are thus urgently warranted. Moreover, it is likely that neuroprotective strategies that directly target neurons may complement immunomodulatory interventions that act on immune ras inhibitor and molecules, so that the two therapeutic approaches can be used in combination. Optic neuritis is a demyelinating inflammation of the optic nerve that typically affects adults ranging from 18 to 45 years old. There is a strong association between optic neuritis and MS, in which optic neuritis is the initial presentation of MS for approximately 20% of MS patients and the risk of developing MS within 15 years after the onset of optic neuritis is approximately 50% (Optic Neuritis Study Group, 2008). Research into optic neuritis is somewhat limited compared with MS research, but it is an important area of investigation that is seeing continuous progress. In preclinical studies, experimental autoimmune encephalomyelitis (EAE), an animal model of MS, is often used to study optic neuritis. Accumulating data indicate that oxidative stress plays a major role in the pathogenesis of MS, optic neuritis, and EAE (Gilgun-Sherki et al., 2004). Indeed, a drastic rise in hydrogen peroxide (H2O2) levels, which was detected by the probe 2′,7′-dichlorofluorescein diacetate (DCFDA), was found in the optic nerves of EAE mice on day six after MOG immunization (Guo et al., 2011). Many studies demonstrate that antioxidants such as lipoic acid, spermidine, and geranylgeranylacetone (GGA) are effective in suppressing inflammation in the spinal cord and optic nerve (Chaudhary et al., 2011, Guo et al., 2009, Guo et al., 2011). Furthermore, gene therapy with antioxidant genes, namely SOD2 and catalase, was effective in reducing optic nerve demyelination, axonal loss, and RGC loss in EAE mice (Qi et al., 2007a, Qi et al., 2007b). These findings suggest that oxidative stress is associated with the pathogenesis of MS and optic neuritis and is an effective target for their treatment. We previously reported that ASK1 deficiency in T cells has no effect on their proliferation, indicating that ASK1 in immune cells has no effect on the severity of MS or optic neuritis (Guo et al., 2010). However, in addition to immune cells, CNS resident glial cells play important roles in demyelinating neuroinflammation (Brosnan and Raine, 2013, Horstmann et al., 2013). Indeed, the ASK1-p38 pathway in astrocytes and microglia plays an essential role in the release of key cytokines during neuroinflammation, including monocyte chemoattractant protein-1 (MCP-1); macrophage inflammatory protein-1 alpha (MIP-1α); regulated on activation, normal T cell expressed and secreted (RANTES); and TNF-α (Guo et al., 2010). In conventional ASK1 KO EAE mice, the reduction of such proinflammatory cytokines as well as a decrease in the upregulation of inducible nitric oxide synthase (iNOS) leads to the suppression of neuroinflammation and of demyelination of the spinal cord and optic nerve. EAE causes a reduction in visual function, which can be assessed by electroretinogram, but ASK1 deficiency ameliorates this visual impairment (Guo et al., 2010), indicating that the inhibition of ASK1 is effective both histologically and functionally. These findings, in combination with in vitro data from primary cultured microglia and astrocytes, suggest that the ASK1 signaling pathway in microglia and astrocytes plays a role in the degeneration of the spinal cord and optic nerve in this model (Guo et al., 2010). Currently, we are examining the roles of ASK1 in various cell types during EAE using cell-type-specific ASK1 KO mice.