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Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation


Mueller, Flavia S; Richetto, Juliet; Hayes, Lindsay N; Zambon, Alice; Pollak, Daniela D; Sawa, Akira; Meyer, Urs; Weber-Stadlbauer, Ulrike (2019). Influence of poly(I:C) variability on thermoregulation, immune responses and pregnancy outcomes in mouse models of maternal immune activation. Brain, Behavior, and Immunity, 80:406-418.

Abstract

Maternal immune activation (MIA) models that are based on administration of the viral mimetic, poly(I:C), arewidely used as experimental tools to study neuronal and behavioral dysfunctions in relation to immune-medi-ated neurodevelopmental disorders and mental illnesses. Evidence from investigations in non-pregnant rodentssuggests that different poly(I:C) products can vary in terms of their immunogenicity, even if they are obtainedfrom the same vendor. The present study aimed at extending these findings to pregnant mice, while also con-trolling various poly(I:C) products for potential contamination with lipopolysaccharide (LPS). We found sig-nificant variability between different batches of poly(I:C) potassium salt obtained from the same vendor (Sigma-Aldrich) in terms of the relative amount of dsRNA fragments in the high molecular weight range (1000–6000nucleotides long) and with regards to their effects on maternal thermoregulation and immune responses inmaternal plasma, placenta and fetal brain. Batches of poly(I:C) potassium salt containing larger amounts of highmolecular weight fragments induced more extensive effects on thermoregulation and immune responses com-pared to batches with minimal amounts of high molecular weight fragments. Consistent with these findings, poly(I:C) enriched for high molecular weight dsRNA (HMW) caused larger maternal and placental immune responsescompared to low molecular weight (LMW) poly(I:C). These variable effects were unrelated to possible LPScontamination. Finally, we found marked variability between different batches of the poly(I:C) potassium salt interms of their effects on spontaneous abortion rates. This batch-to-batch variability was confirmed by threeindependent research groups using distinct poly(I:C) administration protocols in mice. Taken together, thepresent data confirm that different poly(I:C) products can induce varying immune responses and can differen-tially affect maternal physiology and pregnancy outcomes. It is therefore pivotal that researchers working withpoly(I:C)-based MIA models ascertain and consider the precise molecular composition and immunogenicity ofthe product in use. We recommend the establishment of reference databases that combine phenotype data withempirically acquired quality information, which can aid the design, implementation and interpretation of poly(I:C)-based MIA models.

Abstract

Maternal immune activation (MIA) models that are based on administration of the viral mimetic, poly(I:C), arewidely used as experimental tools to study neuronal and behavioral dysfunctions in relation to immune-medi-ated neurodevelopmental disorders and mental illnesses. Evidence from investigations in non-pregnant rodentssuggests that different poly(I:C) products can vary in terms of their immunogenicity, even if they are obtainedfrom the same vendor. The present study aimed at extending these findings to pregnant mice, while also con-trolling various poly(I:C) products for potential contamination with lipopolysaccharide (LPS). We found sig-nificant variability between different batches of poly(I:C) potassium salt obtained from the same vendor (Sigma-Aldrich) in terms of the relative amount of dsRNA fragments in the high molecular weight range (1000–6000nucleotides long) and with regards to their effects on maternal thermoregulation and immune responses inmaternal plasma, placenta and fetal brain. Batches of poly(I:C) potassium salt containing larger amounts of highmolecular weight fragments induced more extensive effects on thermoregulation and immune responses com-pared to batches with minimal amounts of high molecular weight fragments. Consistent with these findings, poly(I:C) enriched for high molecular weight dsRNA (HMW) caused larger maternal and placental immune responsescompared to low molecular weight (LMW) poly(I:C). These variable effects were unrelated to possible LPScontamination. Finally, we found marked variability between different batches of the poly(I:C) potassium salt interms of their effects on spontaneous abortion rates. This batch-to-batch variability was confirmed by threeindependent research groups using distinct poly(I:C) administration protocols in mice. Taken together, thepresent data confirm that different poly(I:C) products can induce varying immune responses and can differen-tially affect maternal physiology and pregnancy outcomes. It is therefore pivotal that researchers working withpoly(I:C)-based MIA models ascertain and consider the precise molecular composition and immunogenicity ofthe product in use. We recommend the establishment of reference databases that combine phenotype data withempirically acquired quality information, which can aid the design, implementation and interpretation of poly(I:C)-based MIA models.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:Immunology, Behavioral Neuroscience, Endocrine and Autonomic Systems, Animal model; Autism; Cytokines; Double-stranded RNA; Infection; Inflammation; Maternal immune activation (MIA); Poly(I:C); Schizophrenia
Language:English
Date:1 August 2019
Deposited On:16 Jan 2020 15:56
Last Modified:16 Jan 2020 15:57
Publisher:Elsevier
ISSN:0889-1591
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.bbi.2019.04.019
PubMed ID:30980948
Project Information:
  • : FunderSNSF
  • : Grant IDPZ00P3_180099
  • : Project TitleMicrobiota-dependent epigenetic programming of specific CNS cell populations
  • : FunderSNSF
  • : Grant ID310030_169544
  • : Project TitleEpigenetic and Transgenerational Mechanisms in Infection-Mediated Neurodevelopmental Disorders

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