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

Autor: Judith A. Pratt, Jaedeok Kwon, Rebecca L. Openshaw, Brian J. Morris, Josef M. Penninger, Jonathan Cavanagh, Alison McColl
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Vascular Endothelial Growth Factor A
0301 basic medicine
sdf-1
Chemokine
medicine.medical_treatment
Neurodevelopment
MAP Kinase Kinase 7
lcsh:RC346-429
Mice
0302 clinical medicine
Pregnancy
TLR3
biology
General Neuroscience
Brain
CXCL3
Cytokine
Neurology
Prenatal Exposure Delayed Effects
Cytokines
Female
medicine.medical_specialty
Interferon Inducers
Poly(I:C)
MAP Kinase Signaling System
Immunology
Mice
Transgenic
CCL5
RS
RANTES
03 medical and health sciences
Cellular and Molecular Neuroscience
Immune system
Internal medicine
medicine
Animals
CXCL10
lcsh:Neurology. Diseases of the nervous system
Fetus
Research
Mice
Inbred C57BL
Disease Models
Animal
Poly I-C
030104 developmental biology
Endocrinology
Gene Expression Regulation
ip-10
Poly(IC)
Schizophrenia
biology.protein
030217 neurology & neurosurgery
Zdroj: Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-11 (2019)
Journal of Neuroinflammation
ISSN: 1742-2094
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1408-5) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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