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Xiaoli Guo, Atsuko Kimura, Kazuhiko Namekata, Chikako Harada, Takayuki Harada; Pathogenic roles of glial ASK1 signaling in neuroinflammation. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2395.
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© ARVO (1962-2015); The Authors (2016-present)
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in various neurodegenerative diseases. However, cell type-specific roles of ASK1 during neuroinflammation remain unknown. In the present study, we investigated the roles of ASK1 in different cell types during neuroinflammation by using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE).
ASK1flox/flox mice were crossed with Lck-Cre+, Cd11c-Cre+, LysM-Cre+, GFAP-Cre+ or CX3CR1-CreER mice to generate five lines of double-transgenic mice, namely T cell-, dendritic cell-, microglia/macrophage-, astrocyte- or microglia-specific conditional knockout (CKO) lines. The resulting CKO mice were named as ASK1Lck KO, ASK1Cd11c KO, ASK1LysM KO, ASK1GFAP KO, or ASK1CX3CR1 KO mice for simplicity. EAE was induced in female CKO and wild-type (WT) mice at 6-8 week old by immunization with a myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, and clinical scores were evaluated daily. Histopathological analysis of the optic nerve and spinal cord was performed. Microglia and astrocytes were cultured and used for molecular mechanism analysis. Microarray and qPCR analysis were used to examine gene expression levels.
The severity of paralytic symptoms in ASK1Lck KO EAE and ASK1Cd11c KO EAE mice were comparable to WT EAE mice, and the clinical symptoms observed in ASK1LysM KO EAE and ASK1GFAP KO EAE mice were ameliorated compared with WT EAE mice. Moreover, the ASK1LysM KO EAE mice showed a reduction in clinical scores from the early stage of the disease, while ASK1GFAP KO EAE mice only showed a reduction during the later stage of the disease. The levels of demyelination observed in the optic nerves of ASK1LysM KO EAE and ASK1GFAP KO EAE mice were milder than the level of demyelination found in WT EAE mice. We found that ASK1 signaling in microglia promoted its polarization towards pro-inflammatory microglia, macrophage infiltration into the central nervous system, and stimulated the induction of an A1 phenotype in astrocytes. Furthermore, ASK1 signaling in astrocytes recruits and activates microglia/macrophages in the later stage of EAE, which contributes, at least partly, to maintaining disease.
Glial ASK1 might be a promising therapeutic target for reducing neuroinflammation.
This is a 2021 ARVO Annual Meeting abstract.
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