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

• Published in: Brain, 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
• Language: English
• 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)
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2016.11.007

•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.