Innate and Adaptive Immune Consequences of Necroptosis

坏死性凋亡的先天性和适应性免疫后果

基本信息

批准号：
10196978
负责人：
Julie Magarian Blander
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196978
关键词：
Acute Lung Injury Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Antigens Apoptosis Apoptotic Atherosclerosis Autoimmune Diseases Autoimmunity Brain Ischemia CASP8 gene CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Death Cell Differentiation process Cell division Cell membrane Cell physiology Cells Cessation of life Characteristics Chronic Chronic lung disease Complex Crohn&apos s disease Development Diet Digestive System Disorders Disease Down-Regulation Embryo Environmental Risk Factor Epithelial Epithelial Cells Equilibrium Event Foundations Functional disorder Gene Expression Profile Gene Expression Profiling Generations Genetic Predisposition to Disease Genetic Transcription Genetically Engineered Mouse Homeostasis Human Immune Immune Tolerance Immune system Immunity Immunosuppression In Vitro Infection Infection Control Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Innate Immune System Intestines Ischemia Knowledge Lamina Propria Life Style Lymphoid Cell Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Mononuclear Mucous Membrane Multiple Sclerosis Mus Myocardial Ischemia Names Nature Nerve Degeneration Normal tissue morphology Organ Organ Model Organ failure Parkinson Disease Pathologic Pathology Pathway interactions Patients Pattern Phagocytes Phagocytosis Phosphotransferases Physiology Population Process Production Protein-Serine-Threonine Kinases Proteins Publishing RIPK1 gene RIPK3 gene Reporting Sampling Signal Transduction Small Intestines Sterility Swelling Systemic Lupus Erythematosus T cell differentiation TNF gene Therapeutic Intervention Tissues Transgenes Ulcerative Colitis Viral Work adaptive immune response autoimmune lymphoproliferative syndrome base chronic inflammatory disease commensal microbes cytokine design dimer genome wide association study imprint in vivo imaging inflammatory disease of the intestine innate immune function intestinal epithelium intestinal homeostasis macrophage mesenteric lymph node microbiota mouse model nervous system disorder novel novel therapeutics pathogenic microbe preservation programs receptor renal ischemia response

项目摘要

PROPOSAL SUMMARY The innate immune system responds to perturbations in tissue homeostasis resultant from infection but also dying cells and tissue damage. Cells die by different modes of programmed cell death including apoptosis and necroptosis. Cell death by apoptosis is a normal component of healthy tissue physiology that is balanced by cell division and maintains normal tissue size and function. Cell death by apoptosis is tolerogenic and non- inflammatory, and contrasts with necroptosis, which is pathological and inflammatory. Necroptosis involves the formation of a complex of receptor interacting serine/threonine protein kinases RIPK1, RIPK3 and the necroptosis effector mixed lineage kinase domain-like protein (MLKL). Up until recently, necroptosis was thought to function primarily in the control of infection and mainly as a fail-safe strategy that counters viral blockade of apoptosis. Studies in mouse models, however, have shown that deficiency in components of the apoptosis machinery such as caspase-8 or FADD leads to embryonic lethality driven by necroptosis and dependent on RIPK3 and MLKL. Other studies using conditional deletion of caspase-8 or FADD in the intestinal epithelium revealed that blocking the pathways that mediate homeostatic apoptosis precipitates intestinal inflammation associated with elevated levels of RIPK3 and necroptosis. Indeed, a notable increase in programmed cell death of intestinal epithelial cells (IEC) has been reported in patients with inflammatory bowel disease (IBD), and this damage is associated with heightened inflammation and increased levels of tumor necrosis factor (TNF)-a, an important mediator of cell death. Using a novel mouse model where we can inducibly trigger necroptosis of IEC, we will determine how IEC necroptosis impacts intestinal homeostasis and we will define the nature of the inflammatory response. Our previous work has established that homeostatic apoptosis within the intestinal epithelium is a major driver of immune suppression and tolerance, imprinting intestinal mononuclear phagocytes (MNP) with ‘suppression of inflammation’ and ‘induction of regulatory CD4 T cell’ transcriptional signatures. Here we will define how necroptosis impacts MNP responses. We will examine the composition and characteristics of the small intestinal MNP population that responds to necroptotic IEC and decipher its function in various innate immune functions relating to the production of inflammatory mediators, modulation of innate lymphoid cell function as well as the CD4 T helper cell differentiation. The knowledge we gain will define how necroptosis drives inflammatory responses by innate and adaptive populations of cells, serve as a roadmap for the consequences of necroptosis in other tissues, and lay the foundation for the development of novel therapeutics for chronic inflammatory diseases such as IBD.

提案摘要先天免疫系统对感染的组织稳态扰动做出反应，但也垂死的细胞和组织损伤。细胞因不同模式的程序性细胞死亡而死，包括凋亡和坏死性。细胞凋亡的细胞死亡是健康组织生理学的正常成分，它是由细胞平衡的分裂并保持正常的组织大小和功能。细胞凋亡的细胞死亡是耐受性的，非 - 炎症，并与坏死作用形成鲜明对比，这是病理和炎症性的。坏死性涉及相互作用的丝氨酸/苏氨酸蛋白激酶RIPK1，RIPK3和RIPK3的形成坏死作用效应子混合谱系激酶结构域样蛋白（MLKL）。直到最近，还认为坏死性在控制感染的控制中起主要作用，主要是反对病毒阻滞的故障安全策略凋亡。然而，在小鼠模型中的研究表明，细胞凋亡的成分缺乏诸如caspase-8或FADD之类的机械导致胚胎致死性驱动，并依赖于 RIPK3和MLKL。其他研究使用肠上皮中caspase-8或FADD的条件缺失的研究发现阻止介导稳态凋亡会导致肠道炎症的途径与RIPK3水平升高和坏死性相关。确实，编程细胞死亡显着增加肠上皮细胞（IEC）已有报道损害与感染的增强和肿瘤坏死因子（TNF）-a的水平增加有关细胞死亡的重要介质。使用新型的小鼠模型，我们可以诱导触发IEC的坏死性，我们将确定IEC坏死性如何影响肠内稳态，我们将定义的性质炎症反应。我们以前的工作已经确定了肠内的稳态凋亡上皮是免疫抑制和耐受性的主要驱动力，印记肠单核吞噬细胞（MNP）带有“注射抑制”和“诱导调节性CD4 T细胞”的转录特征。这里我们将定义坏死性如何影响MNP反应。我们将研究对坏死性IEC响应并在各种先天的功能中响应其功能的小肠道MNP种群与产生炎症介质有关的免疫功能，先天性淋巴样细胞的调节功能以及CD4 T辅助细胞分化。我们获得的知识将定义坏死性驱动先天和适应性细胞的炎症反应，作为路线图其他组织中坏死性的后果，并为开发新疗法奠定了基础对于慢性炎症性疾病，例如IBD。