JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk

Openshaw, R. L. , Kwon, J., McColl, A., Penninger, J. M., Cavanagh, J. , Pratt, J. A. and Morris, B. J. (2019) JNK signalling mediates aspects of maternal immune activation: importance of maternal genotype in relation to schizophrenia risk. Journal of Neuroinflammation, 16(1), 18. (doi: 10.1186/s12974-019-1408-5) (PMID:30691477) (PMCID:PMC6350402)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Openshaw, Rebecca Louise and Pratt, Dr Judith and Kwon, Jaedeok and Cavanagh, Professor Jonathan and McColl, Dr Alison and Morris, Professor Brian
Authors: Openshaw, R. L., Kwon, J., McColl, A., Penninger, J. M., Cavanagh, J., Pratt, J. A., and Morris, B. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Journal of Neuroinflammation
Publisher:BioMed Central
ISSN (Online):1742-2094
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of Neuroinflammation 16(1):18
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632343MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL