JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk
Abstract Background Important insight into the mechanisms through which gene-environmental interactions cause schizophrenia can be achieved through preclinical studies combining prenatal immune stimuli with disease-related genetic risk modifications. Accumulating evidence associates JNK signalling m...
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doaj-e4491777a70e43c38bdab2c69e8264c62020-11-25T02:12:44ZengBMCJournal of Neuroinflammation1742-20942019-01-0116111110.1186/s12974-019-1408-5JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia riskRebecca L. Openshaw0Jaedeok Kwon1Alison McColl2Josef M. Penninger3Jonathan Cavanagh4Judith A. Pratt5Brian J. Morris6Institute of Neuroscience and Psychology, West Medical Building, College of Medical, Veterinary and Life Sciences, University of GlasgowInstitute of Neuroscience and Psychology, West Medical Building, College of Medical, Veterinary and Life Sciences, University of GlasgowInstitute of Inflammation and Immunity, University of GlasgowIMBA, Institute for Molecular Biotechnology of the Austrian Academy of SciencesInstitute of Inflammation and Immunity, University of GlasgowStrathclyde Institute of Pharmacy and Biomedical Sciences, University of StrathclydeInstitute of Neuroscience and Psychology, West Medical Building, College of Medical, Veterinary and Life Sciences, University of GlasgowAbstract Background Important insight into the mechanisms through which gene-environmental interactions cause schizophrenia can be achieved through preclinical studies combining prenatal immune stimuli with disease-related genetic risk modifications. Accumulating evidence associates JNK signalling molecules, including MKK7/MAP2K7, with genetic risk. We tested the hypothesis that Map2k7 gene haploinsufficiency in mice would alter the prenatal immune response to the viral mimetic polyriboinosinic-polyribocytidylic acid (polyI:C), specifically investigating the impact of maternal versus foetal genetic variants. Methods PolyI:C was administered to dams (E12.5), and cytokine/chemokine levels were measured 6 h later, in maternal plasma, placenta and embryonic brain. Results PolyI:C dramatically elevated maternal plasma levels of most cytokines/chemokines. Induction of IL-1β, IL-2, IL-10, IL-12, TNF-α and CXCL3 was enhanced, while CCL5 was suppressed, in Map2k7 hemizygous (Hz) dams relative to controls. Maternal polyI:C administration also increased embryonic brain chemokines, influenced by both maternal and embryonic genotype: CCL5 and CXCL10 levels were higher in embryonic brains from Map2k7 dams versus control dams; for CCL5, this was more pronounced in Map2k7 Hz embryos. Placental CXCL10 and CXCL12 levels were also elevated by polyI:C, the former enhanced and the latter suppressed, in placentae from maternal Map2k7 Hzs relative to control dams receiving polyI:C. Conclusions The results demonstrate JNK signalling as a mediator of MIA effects on the foetus. Since both elevated CXCL10 and supressed CXCL12 compromise developing GABAergic interneurons, the results support maternal immune challenge contributing to schizophrenia-associated neurodevelopmental abnormalities. The influence of Map2k7 on cytokine/chemokine induction converges the genetic and environmental aspects of schizophrenia, and the overt influence of maternal genotype offers an intriguing new insight into modulation of embryonic neurodevelopment by genetic risk.http://link.springer.com/article/10.1186/s12974-019-1408-5NeurodevelopmentChemokineip-10RANTESsdf-1TLR3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rebecca L. Openshaw Jaedeok Kwon Alison McColl Josef M. Penninger Jonathan Cavanagh Judith A. Pratt Brian J. Morris |
spellingShingle |
Rebecca L. Openshaw Jaedeok Kwon Alison McColl Josef M. Penninger Jonathan Cavanagh Judith A. Pratt Brian J. Morris JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk Journal of Neuroinflammation Neurodevelopment Chemokine ip-10 RANTES sdf-1 TLR3 |
author_facet |
Rebecca L. Openshaw Jaedeok Kwon Alison McColl Josef M. Penninger Jonathan Cavanagh Judith A. Pratt Brian J. Morris |
author_sort |
Rebecca L. Openshaw |
title |
JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
title_short |
JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
title_full |
JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
title_fullStr |
JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
title_full_unstemmed |
JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
title_sort |
jnk signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-01-01 |
description |
Abstract Background Important insight into the mechanisms through which gene-environmental interactions cause schizophrenia can be achieved through preclinical studies combining prenatal immune stimuli with disease-related genetic risk modifications. Accumulating evidence associates JNK signalling molecules, including MKK7/MAP2K7, with genetic risk. We tested the hypothesis that Map2k7 gene haploinsufficiency in mice would alter the prenatal immune response to the viral mimetic polyriboinosinic-polyribocytidylic acid (polyI:C), specifically investigating the impact of maternal versus foetal genetic variants. Methods PolyI:C was administered to dams (E12.5), and cytokine/chemokine levels were measured 6 h later, in maternal plasma, placenta and embryonic brain. Results PolyI:C dramatically elevated maternal plasma levels of most cytokines/chemokines. Induction of IL-1β, IL-2, IL-10, IL-12, TNF-α and CXCL3 was enhanced, while CCL5 was suppressed, in Map2k7 hemizygous (Hz) dams relative to controls. Maternal polyI:C administration also increased embryonic brain chemokines, influenced by both maternal and embryonic genotype: CCL5 and CXCL10 levels were higher in embryonic brains from Map2k7 dams versus control dams; for CCL5, this was more pronounced in Map2k7 Hz embryos. Placental CXCL10 and CXCL12 levels were also elevated by polyI:C, the former enhanced and the latter suppressed, in placentae from maternal Map2k7 Hzs relative to control dams receiving polyI:C. Conclusions The results demonstrate JNK signalling as a mediator of MIA effects on the foetus. Since both elevated CXCL10 and supressed CXCL12 compromise developing GABAergic interneurons, the results support maternal immune challenge contributing to schizophrenia-associated neurodevelopmental abnormalities. The influence of Map2k7 on cytokine/chemokine induction converges the genetic and environmental aspects of schizophrenia, and the overt influence of maternal genotype offers an intriguing new insight into modulation of embryonic neurodevelopment by genetic risk. |
topic |
Neurodevelopment Chemokine ip-10 RANTES sdf-1 TLR3 |
url |
http://link.springer.com/article/10.1186/s12974-019-1408-5 |
work_keys_str_mv |
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