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Meningeal type 2 immunity in cortical synapse remodeling during brain development and injury

脑膜2型免疫在大脑发育和损伤过程中皮质突触重塑中的作用

基本信息

批准号：
10573240
负责人：
Anna V Molofsky
金额：
$ 46.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573240
关键词：
Adult Area Automobile Driving Behavior Behavioral Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain region Cell Survival Cell physiology Cells Coculture Techniques Communication Data Defect Development Electrophysiology (science)Fibroblasts Flow Cytometry GABA Receptor Genetic Genetic Transcription Goals Grant Growth Heterogeneity Image Image Cytometry Immune Immune signaling Immunity Immunology Immunophenotyping Impairment In Vitro Inflammation Inhibitory Synapse Injury Interleukin-13 Interleukin-4 Interleukins Life Lymphocyte Lymphocyte Function Lymphoid Cell Macrophage Mediating Meningeal Meninges Microglia Modeling Molecular Morphology Mus Myelogenous Neurodevelopmental Disorder Neuroglia Neurons Neurosciences Organ Pathologic Phenocopy Physiology Play Production Regulation Role Schizophrenia Signal Transduction Slice Social Behavior Source Stromal Cells Supporting Cell Synapses System Testing Three-Dimensional Imaging Tissues Work autism spectrum disorder brain parenchyma brain remodeling brain repair cell type cellular targeting cytokine gain of function healing immune cell infiltrate in vivo injury recovery interleukin-13 receptor loss of function memory recall neuroinflammation novel novel therapeutic intervention postnatal postnatal period receptor recruit repaired response single cell sequencing social synaptic function synaptogenesis transcriptome wound healing

项目摘要

PROJECT SUMMARY Immune signals profoundly influence brain physiology, and immune dysregulation is implicated in neurodevelopmental disorders including autism, schizophrenia, as well as in the remodeling responses engaged after brain injury. As such, there is a critical need to define the cells and molecules that mediate brain-immune communication. Microglia, a type of glial cell, are the dominant immune cell in the brain parenchyma and play key roles in synaptogenesis and synapse refinement during periods of brain remodeling. However, recent discoveries have identified a rich array of immune cells in the meninges and perivascular barrier regions of the brain. This raises the question of how these ‘border’ immune cells in and around the blood brain barrier impact brain remodeling, including during development and after injury. In preliminary data, we demonstrate that a subtype of immune cell known as group 2 innate lymphoid cells (ILC2s) expand and are activated in the developing brain meninges and larger perivascular areas. They secrete their canonical effector cytokine Interleukin-13 with a peak at postnatal days 5-12, which coincides with a robust period of synapse refinement. During development, we show that genetic depletion of ILC2s impaired cortical inhibitory synapse function consistent with defects in GABA receptor subunit composition. These mice had impacts in social recall memory in adulthood. Importantly, global deletion of the IL-4/IL-13 receptor phenocopied these synaptic defects, whereas exogenous IL-13 had the opposite effects. Aim 1 will determine the cellular targets and impacts of IL-13 signaling that mediate these synaptic and behavioral effects in development, based on preliminary data showing that microglia and border associated macrophages express high levels of the IL-13 receptor, and have transcriptional and morphologic responses to IL-13. In preliminary data to Aim 2, we identify a stromal fibroblast niche where ILC2s reside within the developing meninges and use single cell sequencing to define stromal ‘adventitial fibroblasts’ that produce ILC2-supporting signals. We demonstrate that these fibroblasts are sufficient to support ILC2 expansion in vitro, and that they produce the ILC2-regulating signals Interleukin-33. Aim 2 will determine how the meningeal stromal niche supports ILC2 expansion and IL-13 production in vivo, including testing the role of meningeal derived IL-33. In preliminary data to Aim 3, we find that meningeal ILC2s become reactivated and expand after photothrombotic brain injury, limiting post-injury hyperexcitability and damage and promoting the expansion of protective microglial subsets. Aim 3 will determine the impact of ILC2s, IL-13, and their downstream targets in inhibitory synapse remodeling during injury recovery. We will test the alterations in the meninges that sustain this ILC2 expansion and test the hypothesis that IL-33 signaling during damage is required for these changes. Together, these studies will help to define how immune cells in the brain borders impact the developing brain and how these may drive both beneficial and pathologic responses during development and neuroinflammation.

项目总结