Functional Role of IL-6 in Fetal Brain Development and Abnormal Behavior

IL-6 在胎儿大脑发育和异常行为中的功能作用

• 批准号: 8414916
• 负责人: Elaine Hsiao
• 金额: $ 2.26万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414916
• 关键词: Adult; Animal Model; Autistic Disorder; Behavior; Behavioral; Biological Assay; Brain; Brain Pathology; Cells; Defect; Development; Disease; Double-Stranded RNA; Embryo; Endocrine; Environmental Risk Factor; Goals; Human; Immune system; Incidence; Infection; Inflammatory Response; Injection of therapeutic agent; Interleukin-6; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Mus; Neurons; Pathway interactions; Patients; Phosphorylation; Placenta; Poly I-C; Process; Recombinant Interleukins; Research; Research Project Grants; Respiratory Tract Infections; Risk; Risk Factors; Role; STAT1 gene; STAT3 gene; Schizophrenia; Signal Transduction; Site; Staging; Susceptibility Gene; Transgenes; Viral; beta-Galactosidase; cell type; cytokine; endophenotype; environmental agent; fetal; fetus cell; immune activation; insight; mouse model; neurodevelopment; neuropathology; non-genetic; offspring; postnatal; pregnant; promoter; relating to nervous system; response; transcription factor

Maternal infection is an environmental factor that can increase the incidence of autism and schizophrenia in the offspring. In an animal model of this risk factor, respiratory infection of pregnant mice yields offspring that develop behavioral abnormalities and neuropathology consistent with those observed in autistic and schizophrenic patients. These changes can be mimicked by maternal injection of the dsRNA, poly(I:C), which evokes an anti-viral inflammatory response. Recent studies have shown that the cytokine interleukin-6 (IL-6) is necessary and sufficient and necessary for mediating the development of behavioral and transcriptional changes in this maternal immune activation (MIA) model. While IL-6 is critical for mediating the effects of MIA, the mechanism by which IL-6 acts to alter neural development is unknown. We recently demonstrated that, shortly after MIA, maternally-derived IL-6 in the placenta mediates the activation of fetal cells in the placental, and subsequent changes levels of important endocrine factors. However, elucidating the mechanism of IL-6 action in altering fetal brain development is complicated by the fact that IL-6 is also upregulated in the fetal brain after MIA. This project will investigate the pathway of IL-6 action in mediating the development of abnormal behaviors in MIA offspring. We will identify the cells that are responsive to, and activated by, MIA-induced IL-6 in the placenta and embryonic brain. We will localize IL-6Ra promoter activity in mice carrying an IL-6Ra-beta-galactosidase transgene to determine where in the fetal brain and placenta IL-6Ra is expressed. We will then use immunohistochemical methods to detect downstream responses of IL-6Ra activation, including phosphorylation of the transcription factors, STAT3 and STAT1. Importantly, this project will pinpoint specific regions and cells for which IL-6 action is critical for the development of autistic and schizophrenic endophenotypes. We will knockout IL-6R in particular cell types and regions in the fetal brain and placenta and assay behavior to determine where IL-6 action acts to alter fetal brain development. The long-term goals are to elucidate the molecular mechanisms by which IL-6 causes behavioral abnormalities relevant for autism and schizophrenia.

孕产妇感染是一种环境因素，可以增加后代自闭症和精神分裂症的发生率。在这种危险因素的动物模型中，怀孕小鼠的呼吸道感染产生了后代，这种后代与自闭症和精神分裂症患者中观察到的行为异常和神经病理学相一致。这些变化可以通过孕产妇注入dsRNA，poly（i：c）来模仿，这引起了抗病毒炎症反应。最近的研究表明，对于介导该母体免疫激活（MIA）模型中行为和转录变化的发展，细胞因子白介素6（IL-6）是必要的，足够的和必要的。尽管IL-6对于介导MIA的作用至关重要，但IL-6可以改变神经发育的机制尚不清楚。我们最近证明，在MIA之后不久，胎盘中的母体衍生的IL-6介导了胎盘细胞在胎盘中的激活，随后改变了重要的内分泌因子的水平。然而，阐明IL-6作用在改变胎儿脑发育方面的机制是因为MIA后IL-6在胎儿大脑中也被上调的事实变得复杂。该项目将研究IL-6行动在介导MIA后代异常行为发展的途径。我们将确定对胎盘和胚胎大脑中MIA诱导的IL-6响应并激活的细胞。我们将将IL-6RA启动子活性定位在携带IL-6RA-beta-galactosidase transgene的小鼠中，以确定表达胎儿脑和胎盘IL-6RA的位置。然后，我们将使用免疫组织化学方法检测IL-6RA激活的下游反应，包括转录因子STAT3和STAT1的磷酸化。重要的是，该项目将确定IL-6作用对于自闭症和精神分裂症内表型至关重要的特定区域和细胞。我们将在胎儿大脑和胎盘中的特定细胞类型和区域以及测定行为中敲除IL-6R，以确定IL-6作用在改变胎儿脑发育的位置。长期目标是阐明IL-6引起与自闭症和精神分裂症相关的行为异常的分子机制。

项目成果

IL-33 Changes Our "Gut Feelings" about Serotonin.

• DOI: 10.1016/j.immuni.2020.12.007
• 发表时间: 2021-01
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Lewis W Yu;E. Hsiao

Mitochondrial and Purinergic Dysregulation Promote Abnormal Behavior in Mice.

• DOI: 10.1016/j.it.2019.12.007
• 发表时间: 2020-01
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: P. Fang;E. Hsiao

Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.

• DOI: 10.1016/j.cell.2013.11.024
• 发表时间: 2013-12-19
• 期刊: Cell
• 影响因子: 64.5
• 作者: Hsiao EY;McBride SW;Hsien S;Sharon G;Hyde ER;McCue T;Codelli JA;Chow J;Reisman SE;Petrosino JF;Patterson PH;Mazmanian SK
• 通讯作者: Mazmanian SK