The placental interleukin-6 signaling controls fetal brain development and behavior
Open accessAbstract
Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6ra fl/fl), and tested offspring of Cyp19-Cre+;Il6ra fl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6ra fl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.
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Increased levels of IL-6 alone recapitulate aspects of ASD pathophysiology.
“Importantly, increased levels of IL-6 alone recapitulate aspects of ASD pathophysiology [138, 142, 143].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [143]
Placental interleukin-6 mediates the maternal infection-induced ASD risk to the developing fetus.
“Placental interleukin-6 (IL-6), a pro-inflammatory cytokine, was shown to mediate the maternal infection-induced ASD risk to the developing fetus.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [71]
Progeny of MIA mice develop phenotypes consistent with ASD, whereas mice with selective deletion of IL-6 in placental trophoblasts had offspring that did not display these neurobiological or behavioral abnormalities.
“Whereas progeny of MIA mice develop phenotypes consistent with ASD, those mice with selective deletion of IL-6 in placental trophoblasts had offspring that did not display these neurobiological or behavioral abnormalities 71.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [71]
Mouse studies have shown evidence that the link between maternal inflammation and ASD development may involve placental inflammation.
“Mouse studies have shown evidence that the link between maternal inflammation and ASD development may involve placental inflammation.”
From Gastrointestinal Issues and Autism Spectrum Disorder (2020) · cites this paper as [71]
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- Authors
- Wu, W.-L., Hsiao, E. Y., Yan, Z., Mazmanian, S. K., & Patterson, P. H.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Wu, Wei-Li
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 62
- Pages
- 11-23
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5373986
- OpenAlex
- W2553830639
- Cited by
- 275
- References
- 76
- Citations by year
- 2026: 24 · 2025: 30 · 2024: 32 · 2023: 30 · 2022: 33 · 2021: 38 · 2020: 26 · 2019: 32 · 2018: 19 · 2017: 10 · 2016: 1
- FWCI
- 6.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- NIH (5P50MH086383-04)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- maternal immune activation, interleukin-6, IL-6 receptor alpha, placenta, trophoblast, fetal brain development, autism risk, neuroinflammation, offspring behavior, neurodevelopmental disorders
- MeSH terms
- Animals, Behavior, Animal, Brain, Female, Placenta, Pregnancy, Signal Transduction, Interleukin-6, Mice, Knockout, Receptors, Interleukin-6, Fetal Development, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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