Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

Kwon, J., Suessmilch, M., McColl, A., Cavanagh, J. and Morris, B. J. (2021) Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk. Scientific Reports, 11, 23841. (doi: 10.1038/s41598-021-03216-9) (PMID:34903784) (PMCID:PMC8668921)

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Abstract

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

Item Type:Articles
Additional Information:Funding: The research leading to these results received funding from the Wellcome Trust under Grant reference 104025/Z/14/Z.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kwon, Jaedeok and Cavanagh, Professor Jonathan and McColl, Dr Alison and Suessmilch, Maria and Morris, Professor Brian
Authors: Kwon, J., Suessmilch, M., McColl, A., Cavanagh, J., and Morris, B. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
Copyright Holders:Copyright © The Author(s) 2021
First Published:First published in Scientific Reports 11: 23841
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171331Consortium of Neuroimmunology of Mood Disorders and Alzheimer's DiseaseJonathan CavanaghWellcome Trust (WELLCOTR)104025/Z/14/ZHW - Mental Health and Wellbeing