Cargando…

Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia

BACKGROUND: The interaction between the membrane glycoprotein, CD200 and its cognate receptor CD200 receptor (CD200R), has been shown to play a role in maintaining microglia in a quiescent state. There is evidence of increased activation under resting and stimulated conditions in microglia prepared...

Descripción completa

Detalles Bibliográficos
Autores principales: Lyons, Anthony, Downer, Eric J, Costello, Derek A, Murphy, Niamh, Lynch, Marina A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514341/
https://www.ncbi.nlm.nih.gov/pubmed/22642833
http://dx.doi.org/10.1186/1742-2094-9-107
_version_ 1782252020720205824
author Lyons, Anthony
Downer, Eric J
Costello, Derek A
Murphy, Niamh
Lynch, Marina A
author_facet Lyons, Anthony
Downer, Eric J
Costello, Derek A
Murphy, Niamh
Lynch, Marina A
author_sort Lyons, Anthony
collection PubMed
description BACKGROUND: The interaction between the membrane glycoprotein, CD200 and its cognate receptor CD200 receptor (CD200R), has been shown to play a role in maintaining microglia in a quiescent state. There is evidence of increased activation under resting and stimulated conditions in microglia prepared from CD200-deficient mice compared with wild-type mice, whereas activation of the receptor by CD200 fusion protein (CD200Fc) ameliorates inflammatory changes which are evident in the central nervous system (CNS) of the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) and also in the hippocampus of aged rats. Additionally, an inverse relationship between microglial activation and expression of CD200 has been observed in animals treated with lipopolysaccharide (LPS) or amyloid-β (Aβ). METHODS: We assessed the effect of CD200R activation by CD200Fc on Aβ-induced production of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) and the expression of microglial activation markers, CD68 and CD40 in cultured glia. The role played by downstream of tyrosine kinase 2 (Dok2) phosphorylation in mediating the effects of CD200R activation was evaluated by siRNA knockdown of Dok2. To further examine the impact of inflammatory changes on synaptic plasticity, the effect of CD200Fc on Aβ-induced impairment of long-term potentiation (LTP) in the CA1 region of hippocampal slices was also investigated. RESULTS: We demonstrate that Aβ-induced increases in IL-1β, TNFα, CD68 and CD40 were inhibited by CD200Fc. The evidence suggests that Dok2 phosphorylation is a key factor in mediating the effect of CD200Fc, since Dok2 knockdown by siRNA abrogated its effects on microglial activation and inflammatory cytokine production. Consistent with evidence that inflammatory changes negatively impact on LTP, we show that the Aβ-induced impairment of LTP was attenuated by CD200Fc. CONCLUSIONS: The findings suggest that activation of CD200R and Dok2 is a valuable strategy for modulating microglial activation and may have therapeutic potential in neurodegenerative conditions.
format Online
Article
Text
id pubmed-3514341
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-35143412012-12-05 Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia Lyons, Anthony Downer, Eric J Costello, Derek A Murphy, Niamh Lynch, Marina A J Neuroinflammation Research BACKGROUND: The interaction between the membrane glycoprotein, CD200 and its cognate receptor CD200 receptor (CD200R), has been shown to play a role in maintaining microglia in a quiescent state. There is evidence of increased activation under resting and stimulated conditions in microglia prepared from CD200-deficient mice compared with wild-type mice, whereas activation of the receptor by CD200 fusion protein (CD200Fc) ameliorates inflammatory changes which are evident in the central nervous system (CNS) of the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) and also in the hippocampus of aged rats. Additionally, an inverse relationship between microglial activation and expression of CD200 has been observed in animals treated with lipopolysaccharide (LPS) or amyloid-β (Aβ). METHODS: We assessed the effect of CD200R activation by CD200Fc on Aβ-induced production of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) and the expression of microglial activation markers, CD68 and CD40 in cultured glia. The role played by downstream of tyrosine kinase 2 (Dok2) phosphorylation in mediating the effects of CD200R activation was evaluated by siRNA knockdown of Dok2. To further examine the impact of inflammatory changes on synaptic plasticity, the effect of CD200Fc on Aβ-induced impairment of long-term potentiation (LTP) in the CA1 region of hippocampal slices was also investigated. RESULTS: We demonstrate that Aβ-induced increases in IL-1β, TNFα, CD68 and CD40 were inhibited by CD200Fc. The evidence suggests that Dok2 phosphorylation is a key factor in mediating the effect of CD200Fc, since Dok2 knockdown by siRNA abrogated its effects on microglial activation and inflammatory cytokine production. Consistent with evidence that inflammatory changes negatively impact on LTP, we show that the Aβ-induced impairment of LTP was attenuated by CD200Fc. CONCLUSIONS: The findings suggest that activation of CD200R and Dok2 is a valuable strategy for modulating microglial activation and may have therapeutic potential in neurodegenerative conditions. BioMed Central 2012-05-29 /pmc/articles/PMC3514341/ /pubmed/22642833 http://dx.doi.org/10.1186/1742-2094-9-107 Text en Copyright ©2012 Lyons et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Lyons, Anthony
Downer, Eric J
Costello, Derek A
Murphy, Niamh
Lynch, Marina A
Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title_full Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title_fullStr Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title_full_unstemmed Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title_short Dok2 mediates the CD200Fc attenuation of Aβ-induced changes in glia
title_sort dok2 mediates the cd200fc attenuation of aβ-induced changes in glia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514341/
https://www.ncbi.nlm.nih.gov/pubmed/22642833
http://dx.doi.org/10.1186/1742-2094-9-107
work_keys_str_mv AT lyonsanthony dok2mediatesthecd200fcattenuationofabinducedchangesinglia
AT downerericj dok2mediatesthecd200fcattenuationofabinducedchangesinglia
AT costellodereka dok2mediatesthecd200fcattenuationofabinducedchangesinglia
AT murphyniamh dok2mediatesthecd200fcattenuationofabinducedchangesinglia
AT lynchmarinaa dok2mediatesthecd200fcattenuationofabinducedchangesinglia