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Xiaoli Guo, Kazuhiko Namekata, Yuriko Azuchi, Atsuko Kimura, Takahiko Noro, Chikako Harada, Takayuki Harada; Dock10 deficiency reduces neuroinflammation in optic neuritis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3348.
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© ARVO (1962-2015); The Authors (2016-present)
Dock proteins, a class of guanine nucleotide exchange factors (GEFs) for Rho GTPases, can be divided into four families: Dock-A, B, C and D family. Current knowledge on each Dock family is still limited. In the present study, we investigated the effects of Dock-D family, which includes Dock9, Dock10 and Dock11, on optic neuritis that is usually associated with multiple sclerosis (MS) by using an animal model of MS, experimental autoimmune encephalomyelitis (EAE).
Three lines of knockout (KO) mice, namely Dock9 KO, Dock10 KO and Dock11 KO mice were generated. Splenic cells were isolated for FACS analysis and a CD3-stimulated T cell proliferation assay. EAE was induced in female KO 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. Multifocal electroretinograms were recorded using a VERIS 6.0 system. Histopathological analysis of the retina, optic nerve and spinal cord was performed. Bone-marrow-derived macrophage (BMDM) and astrocytes were cultured and used for possible mechanism analysis. Concentrations of monocyte chemoattractant protein-1 (MCP1) were measured by an enzyme-linked immunosorbent assay (ELISA).
Among the three KO mouse lines, only Dock10 KO mice showed difference to WT mice. The extents of demyelination and neuroinflammation, as revealed by histopathological analysis, were decreased in the optic nerve and spinal cord of Dock10 KO EAE mice. Consistently, the clinical scores of Dock10 KO EAE mice were ameliorated in the late phase of the disease compared with WT mice. Interestingly, the impaired visual function and reduced cell numbers in the retina observed in WT EAE mice were also observed in Dock10 KO EAE mice in a similar manner. These results indicate that retinal cell death occurs at an early phase of EAE and so the impaired visual function cannot be restored. FACS analysis demonstrated that there was no difference in immune cell development and CD3-stimulated T cell proliferation in each KO line compared with WT mice. However, Dock10-deficient BMDM showed reduced migration ability and MCP1 production by astrocytes was decreased with Dock10 deficiency, which might partially explain for the reduced neuroinflammation in Dock10 KO EAE mice.
Dock10, but not Dock9 and Dock11, is involved in neuroinflammation during optic neuritis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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