The placental interleukin-6 signaling controls fetal brain development and behavior

•IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA.•Placental IL-6Rα knockout prevents MIA induced inflammatory responses in placental-fetal axis.•MIA-induced behavioral abnormalities are prevented in placental IL-6Rα knockout mice.•MIA-induced cerebellar neurop...

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Published inBrain, behavior, and immunity Vol. 62; pp. 11 - 23
Main Authors Wu, Wei-Li, Hsiao, Elaine Y., Yan, Zihao, Mazmanian, Sarkis K., Patterson, Paul H.
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier Inc 01.05.2017
Subjects
Allergy and Immunology
Animals
Autism spectrum disorder (ASD)
Behavior, Animal - physiology
Brain - embryology
Brain - metabolism
Female
Fetal Development - physiology
Hindbrain development
Interleukin-6 (IL-6)
Interleukin-6 - metabolism
Maternal immune activation (MIA)
Maternal-placental-fetal axis
Mice
Mice, Knockout
Placenta
Placenta - metabolism
Pregnancy
Psychiatry
Purkinje cells
Receptors, Interleukin-6 - genetics
Receptors, Interleukin-6 - metabolism
Signal Transduction - physiology
Hindbrain development
Maternal-placental-fetal axis
Placenta
Autism spectrum disorder (ASD)
Purkinje cells
Maternal immune activation (MIA)
Interleukin-6 (IL-6)
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Abstract •IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA.•Placental IL-6Rα knockout prevents MIA induced inflammatory responses in placental-fetal axis.•MIA-induced behavioral abnormalities are prevented in placental IL-6Rα knockout mice.•MIA-induced cerebellar neuropathologies are prevented in placental IL-6Rα knockout mice. 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+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/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+;Il6rafl/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.
AbstractList 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 ), and tested offspring of Cyp19-Cre ;Il6ra 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 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.
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.
•IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA.•Placental IL-6Rα knockout prevents MIA induced inflammatory responses in placental-fetal axis.•MIA-induced behavioral abnormalities are prevented in placental IL-6Rα knockout mice.•MIA-induced cerebellar neuropathologies are prevented in placental IL-6Rα knockout mice. 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+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/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+;Il6rafl/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.
Highlights • IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA. • Placental IL-6Rα knockout prevents MIA induced inflammatory responses in placental-fetal axis. • MIA-induced behavioral abnormalities are prevented in placental IL-6Rα knockout mice. • MIA-induced cerebellar neuropathologies are prevented in placental IL-6Rα knockout mice.
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+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/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+;Il6rafl/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.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+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/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+;Il6rafl/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.
Author Mazmanian, Sarkis K.
Hsiao, Elaine Y.
Patterson, Paul H.
Wu, Wei-Li
Yan, Zihao
AuthorAffiliation b Department of Integrative Biology & Physiology, University of California, Los Angeles, 610 Charles E. Young Drive, Los Angeles, CA, 90095, USA
a Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA, 91125, USA
AuthorAffiliation_xml – name: b Department of Integrative Biology & Physiology, University of California, Los Angeles, 610 Charles E. Young Drive, Los Angeles, CA, 90095, USA
– name: a Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA, 91125, USA
Author_xml – sequence: 1
  givenname: Wei-Li
  surname: Wu
  fullname: Wu, Wei-Li
  email: wlwu@caltech.edu
  organization: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
– sequence: 2
  givenname: Elaine Y.
  surname: Hsiao
  fullname: Hsiao, Elaine Y.
  email: ehsiao@ucla.edu
  organization: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
– sequence: 3
  givenname: Zihao
  surname: Yan
  fullname: Yan, Zihao
  email: Zihao_Yan@hms.harvard.edu
  organization: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
– sequence: 4
  givenname: Sarkis K.
  surname: Mazmanian
  fullname: Mazmanian, Sarkis K.
  email: sarkis@caltech.edu
  organization: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
– sequence: 5
  givenname: Paul H.
  surname: Patterson
  fullname: Patterson, Paul H.
  email: php@caltech.edu
  organization: Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27838335$$D View this record in MEDLINE/PubMed
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Keywords Hindbrain development
Maternal-placental-fetal axis
Placenta
Autism spectrum disorder (ASD)
Purkinje cells
Maternal immune activation (MIA)
Interleukin-6 (IL-6)
Language English
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This study is dedicated to Paul H. Patterson, who conceived and led the project prior to his passing in 2014.
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Snippet •IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA.•Placental IL-6Rα knockout prevents MIA induced inflammatory responses...
Highlights • IL-6 downstream signaling is activated in specific regions of fetal hindbrain after MIA. • Placental IL-6Rα knockout prevents MIA induced...
Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain...
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StartPage 11
SubjectTerms Allergy and Immunology
Animals
Autism spectrum disorder (ASD)
Behavior, Animal - physiology
Brain - embryology
Brain - metabolism
Female
Fetal Development - physiology
Hindbrain development
Interleukin-6 (IL-6)
Interleukin-6 - metabolism
Maternal immune activation (MIA)
Maternal-placental-fetal axis
Mice
Mice, Knockout
Placenta
Placenta - metabolism
Pregnancy
Psychiatry
Purkinje cells
Receptors, Interleukin-6 - genetics
Receptors, Interleukin-6 - metabolism
Signal Transduction - physiology
Title The placental interleukin-6 signaling controls fetal brain development and behavior
URI https://www.clinicalkey.com/#!/content/1-s2.0-S0889159116304974
https://www.clinicalkey.es/playcontent/1-s2.0-S0889159116304974
https://dx.doi.org/10.1016/j.bbi.2016.11.007
https://www.ncbi.nlm.nih.gov/pubmed/27838335
https://www.proquest.com/docview/1839115748
https://pubmed.ncbi.nlm.nih.gov/PMC5373986
Volume 62
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