Group 2 innate lymphoid cells in tissue regeneration

组织再生中的第 2 组先天淋巴细胞

• 批准号: 9375969
• 负责人: Sergio Armando Villalta
• 金额: $ 22.25万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375969
• 关键词: Ablation; Acute; Address; Allergens; Alpha Cell; Amphiregulin; Anatomy; Anti-inflammatory; Antigens; Autoimmune Diseases; Autoimmunity; Biological Assay; Biological Models; Biology; Cell Communication; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Coculture Techniques; Communities; Complex; Data; Degenerative Disorder; Development; Disease; Disease Outcome; Duchenne muscular dystrophy; Epidermal Growth Factor Receptor; Epithelial; Equilibrium; Frequencies; GATA3 gene; Genetic; Growth; Growth Factor; Homeostasis; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin-Dependent Diabetes Mellitus; Interleukin-13; Interleukin-2; Interleukin-4; Interleukin-5; Interleukins; Intervention; Investigation; Knowledge; Location; Lung; Lymphoid Cell; Mediating; Modeling; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Dystrophies; Myopathy; Natural Immunity; Natural regeneration; Pathogenesis; Pathway interactions; Pharmacology; Physiological; Play; Population; Production; Receptor Cell; Regenerative Medicine; Regenerative response; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resources; Role; Signal Transduction; Skeletal Muscle; Stem cells; Sterility; System; TSLP gene; Testing; Tissues; Trauma; Work; adaptive immunity; base; clinical translation; comparative; cytokine; eosinophil; healing; inflammatory modulation; injured; insight; loss of function; macrophage; mdx mouse; mouse model; muscle regeneration; muscular system; neutralizing antibody; novel; novel therapeutics; pathogen; prevent; progenitor; regenerative; repaired; response; stem; stem cell niche; therapeutic target; tissue degeneration; tissue regeneration; tissue repair; tissue trauma

Project Summary/Abstract Our investigation is directed at understanding how group 2 innate lymphoid cells (ILC2s) promote tissue regeneration. Innate and adaptive immunity converge during tissue trauma to play an instrumental role in regulating the balance between pro-inflammatory and anti-inflammatory responses that promote injury and regeneration, respectively. In previous studies examining the role of regulatory T cells (Tregs) in tissue regeneration, we used IL-2 complex (IL-2c) to increase Tregs during tissue degeneration, and found that IL-2c robustly increased Treg numbers, resolved tissue inflammation and reduced injury, indicating that Tregs aid in tissue regeneration by modulating the inflammatory response to injured tissue. Recent studies have reported that IL-2c also robustly increases ILC2s, and modulation of tissue inflammatory responses in response to IL-2c treatment were attributed to increases in ILC2s in a mouse model of type 1 diabetes. Based on these observations we will examine the role of ILC2s in tissue regeneration using skeletal muscle as a model system for out investigation. Skeletal muscle provides several advantage including 1) it is a highly regenerative tissue, 2) has a well-defined tissue stem cell niche, and 3) previous studies have shown that innate immunity is important for efficient muscle regeneration. The focus our study is centered at testing the hypothesis that ILC2s promote muscle regeneration through the modulation of type 2 innate inflammatory responses and direct interactions with muscle stem cells that regulate stem proliferation and/or differentiation. In preliminary work, we show that ILC2s are activated by tissue injury, IL-2c significantly increased ILC2s during muscle regeneration, and that IL-2c increases the size of muscle fibers, suggesting that ILC2 regulate muscle regeneration or growth. In specific aim 1, we will characterize the role of ILC2s in muscle regeneration, and examine their capacity to directly regulate the myogenic function of muscle stem cells (mSCs). We predict that ILC2-derived amphiregulin (Areg) directly acts on mSCs to modulate their proliferation and/or differentiation. In specific aim 2, we will examine the capacity of ILC2s to regulate sterile, type 2 innate immunity, which was previously shown to be critical for efficient tissue regeneration. We predict that ILC2s, through their production of IL-5 and IL-13, directly activate eosinophils (Eos) and M2 macrophages, innate immune cells that were both shown to promote muscle regeneration. Collectively, the proposed work promises to advance our understanding of the diverse biology of ILC2s by showing that ILC2s are critical immune cells that guide efficient tissue regeneration by regulating inflammatory responses that promote regeneration, and through direct interaction with tissue stems cells that a required for regeneration. Moreover, our study will reveal new therapeutic pathways that may be targeted to promote regeneration in a broad class of clinical settings, including acute trauma, degenerative disorders and autoimmunity resulting in destruction of tissues.

项目总结/摘要 我们的研究旨在了解第2组先天淋巴样细胞（ILC 2）如何促进组织再生。 先天免疫和适应性免疫在组织创伤期间会聚，在调节平衡中发挥工具性作用 分别促进损伤和再生的促炎和抗炎反应之间的关系。在 以前的研究检查了调节性T细胞（Tcells）在组织再生中的作用，我们使用IL-2复合物（IL-2c）， 在组织变性期间增加Treg，并发现IL-2c强烈增加Treg数量，溶解组织 炎症和减少的损伤，表明TdR通过调节炎症和减少的损伤来帮助组织再生。 对受伤组织的反应。最近的研究已经报道，IL-2c也强烈地增加ILC 2，并且调节IL-2c的表达。 对IL-2c治疗的组织炎症反应归因于IL-2c的小鼠模型中ILC 2的增加。 1型糖尿病基于这些观察结果，我们将研究ILC 2在使用骨骼的组织再生中的作用 肌肉作为我们研究的模型系统。骨骼肌提供了几个优势，包括1）它是一个高度 再生组织，2）有一个明确的组织干细胞龛，3）以前的研究表明，先天性 免疫力对于有效的肌肉再生是重要的。我们研究的重点是检验假设， ILC 2通过调节2型先天性炎症反应促进肌肉再生， 与调节干细胞增殖和/或分化的肌肉干细胞的相互作用。在初步工作中，我们显示 ILC 2被组织损伤激活，IL-2c在肌肉再生过程中显著增加ILC 2，并且IL-2c 增加肌肉纤维的大小，表明ILC 2调节肌肉再生或生长。在具体目标1中，我们 将描述ILC 2在肌肉再生中的作用，并检查其直接调节肌源性 肌肉干细胞（mSCs）我们预测ILC 2衍生的双调蛋白（Areg）直接作用于mSCs， 调节它们的增殖和/或分化。在具体目标2中，我们将审查第二国际劳工委员会的监管能力， 无菌的2型先天免疫，这是以前被证明是有效的组织再生的关键。我们预测 ILC 2通过产生IL-5和IL-13，直接激活嗜酸性粒细胞（Eos）和M2巨噬细胞，先天性 这两种免疫细胞都能促进肌肉再生。总的来说，拟议的工作承诺 通过显示ILC 2是引导免疫细胞的关键免疫细胞， 通过调节促进再生的炎症反应，并通过直接 与再生所需的组织干细胞相互作用。此外，我们的研究将揭示新的治疗方法， 在广泛的临床环境中，包括急性创伤， 导致组织破坏的退行性疾病和自身免疫。