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

• 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
• 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

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.

项目摘要 免疫信号深刻地影响大脑生理学，而免疫失调与 神经发育障碍，包括自闭症，精神分裂症，以及参与重塑反应， 脑损伤后因此，迫切需要定义介导脑免疫的细胞和分子 通信小胶质细胞是胶质细胞的一种，是脑实质中的主要免疫细胞， 在脑重塑期间的突触发生和突触细化中起关键作用。但最近的 这些发现已经鉴定出在脑膜和血管周围屏障区域中丰富的免疫细胞阵列。 个脑袋这就提出了一个问题，即这些“边界”免疫细胞是如何影响血脑屏障的 脑重塑，包括发育期间和损伤后。在初步数据中，我们证明， 称为第2组先天淋巴样细胞（ILC 2）的免疫细胞亚型在体内扩增并被激活 发育中的脑膜和更大的血管周围区域。它们分泌典型的效应细胞因子 白细胞介素-13在出生后第5 - 12天达到峰值，这与突触细化的稳健时期相一致。 在发育过程中，我们发现ILC2的遗传缺失损害了皮质抑制性突触功能， 与GABA受体亚基组成缺陷一致。这些老鼠的社交回忆记忆 在成年期。重要的是，IL-4/IL-13受体的整体缺失表现出这些突触缺陷，而 外源性IL-13具有相反的作用。目的1将确定IL-13信号传导的细胞靶点和影响 在发育过程中介导这些突触和行为效应，基于初步数据显示， 小胶质细胞和边缘相关巨噬细胞表达高水平的IL-13受体，并具有转录激活作用。 和对IL-13的形态学应答。在目标2的初步数据中，我们确定了一个基质成纤维细胞龛， ILC2位于发育中的脑膜内，并使用单细胞测序来确定基质的外膜 产生ILC2支持信号的成纤维细胞。我们证明这些成纤维细胞足以支持 ILC2在体外扩增，并且它们产生ILC2调节信号白细胞介素-33。目标2将决定 脑膜间质小生境如何支持ILC2扩增和体内IL-13产生，包括检测 脑膜来源的IL-33的作用。在目标3的初步数据中，我们发现脑膜ILC2被重新激活， 并在光血栓形成脑损伤后扩张，限制损伤后的过度兴奋和损伤， 保护性小胶质细胞亚群的扩张。目的3将确定ILC2、IL-13及其对人白细胞介素2（IL-2）表达的影响。 在损伤恢复过程中抑制突触重塑的下游靶点。我们将测试的变化， 维持这种ILC2扩增并测试损伤期间需要IL-33信号传导的假设 对于这些变化。总之，这些研究将有助于确定大脑边界中的免疫细胞如何影响大脑的功能。 发育中的大脑以及这些如何在发育过程中驱动有益和病理反应， 神经炎症