Regulation of the severity of neuroinflammation and demyelination by TLR‐ASK1‐p38 pathway

Guo, Xiaoli; Harada, Chikako; Namekata, Kazuhiko; Matsuzawa, Atsushi; Camps, Montserrat; Ji, Hong; Swinnen, Dominique; Jorand-Lebrun, Catherine; Muzerelle, Mathilde; Vitte, Pierre-Alain; Rückle, Thomas; Kimura, Atsuko; Kohyama, Kuniko; Matsumoto, Yoh; Ichijo, Hidenori; Harada, Takayuki

doi:10.1002/emmm.201000103

Cited by 131 publications

(126 citation statements)

References 48 publications

(70 reference statements)

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“…Apoptosis signal-regulating kinase 1 (ASK1) is a TLR-controlled kinase that is known to activate p38 MAPK. Deletion of ASK1 attenuated p38 MAPK activation, EAE severity, and production of proinflammatory cytokines by astrocytes and microglia without affecting peripheral T cell responses, suggesting that ASK1-dependent activation of p38 MAPK glial cells may promote EAE pathogenesis (61). Taken together, these results suggest that p38 MAPK in CNS resident cells likely promotes EAE pathogenesis, but future studies are needed to show this definitively.…”

Section: The Role Of P38 Mapk Signaling In Cns-resident Cells In Eaementioning

confidence: 89%

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

Krementsov

Thornton

Teuscher

et al. 2013

Molecular and Cellular Biology

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Multiple sclerosis (MS), the most common disabling neurologic disease of young adults, is considered a classical T cell-mediated disease and is characterized by demyelination, axonal damage, and progressive neurological dysfunction. The currently available disease-modifying therapies are limited in their efficacy, and improved understanding of new pathways contributing to disease pathogenesis could reveal additional novel therapeutic targets. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is known to be triggered by stress stimuli and to contribute to inflammatory responses. Importantly, a number of recent studies have identified this signaling pathway as a central player in MS and its principal animal model, experimental allergic encephalomyelitis. Here, we review the evidence from mouse and human studies supporting the role of p38 MAPK in regulating key immunopathogenic mechanisms underlying autoimmune inflammatory disease of the central nervous system and the potential of targeting this pathway as a disease-modifying therapy in MS. PATHOGENESIS OF MULTIPLE SCLEROSIS

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Section: The Role Of P38 Mapk Signaling In Cns-resident Cells In Eaementioning

confidence: 89%

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

Krementsov

Thornton

Teuscher

et al. 2013

Molecular and Cellular Biology

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“…Recent studies showed compound K811, a specific ASK1 inhibitor, had a beneficial effect on glial cell activation in experimental autoimmune encephalomyelitis 31 and gastric cancer cell growth in vitro and in vivo. 32 In the present study, administration of compound K811 mimicked the protective effects of ASK1 deficiency in the BCAS mice model.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Toyama

Koibuchi

Uekawa

et al. 2014

ATVB

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of VaD and the development of a clinical therapeutic strategy for VaD are urgent topics for research.Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein (MAP) kinase kinase kinase family, activates MAP kinase kinases, which in turn activate p38 and C-Jun N-terminal (JNK) MAP kinase. Objective-There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions. Approach and Results-A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCASinduced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1 −/− ) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1 −/− mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1 −/− mice. Cerebral nitrotyrosine was increased in wild-type and ASK1 −/− BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1 −/− mice. Conclusions-Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through bloodbrain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment. Figure I in the online-only Data Supplement). Our previous reports showed that ASK1 is involved in angiotensin II-induced vascular endothelial dysfunction and apoptosis, 10 balloon injury-induced vascular neointima formation, 11 and ischemia-induced angiogenesis. 12The potential role of ASK1 in cerebral vasculature/small vessels should be further investigated in relation to VaD. Cerebral ischemia increases cerebral oxidative stress levels 13 and vascular cognitive impairment induced by chronic cerebral ischemia is associated with BBB disruption.14-16 The BBB consists of endothelial cells, basal lamina matrix, astrocyte end-feet, and pericytes. Therefore, in the present study, we hypothesized that ASK1 might be involved in oxidative stress-induced BBB disruption because ...

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“…40,41 As Dock3 protects RGCs from oxidative stress, the combination of Dock3 overexpression and inhibition of ASK1 signaling by a specific inhibitor 42 may be further available for the management of glaucoma. One important point is that glaucoma is a complex disease resulting from the confluence of various factors.…”

Section: -37mentioning

confidence: 99%

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

et al. 2013

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Dedicator of cytokinesis 3 (Dock3), a new member of the guanine nucleotide exchange factors for the small GTPase Rac1, promotes axon regeneration following optic nerve injury. In the present study, we found that Dock3 directly binds to the intracellular C-terminus domain of NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that glutamate/aspartate transporter (GLAST) is a major glutamate transporter in the retina, and RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress, and identifies Dock3 signaling as a potential therapeutic target for both neuroprotection and axonal regeneration.

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Regulation of the severity of neuroinflammation and demyelination by TLR‐ASK1‐p38 pathway

Cited by 131 publications

References 48 publications

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

The Emerging Role of p38 Mitogen-Activated Protein Kinase in Multiple Sclerosis and Its Models

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma

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