Intracellular nucleic acid sensing and age-related chronic inflammation

细胞内核酸传感与年龄相关的慢性炎症

• 批准号: 10329935
• 负责人: Shruti Sharma
• 金额: $ 41.65万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-22 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329935
• 关键词: Address; Adipose tissue; Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Animals; Architecture; Attenuated; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmunity; Autologous; Biology; Brain; Cardiovascular system; Cells; ChIP-seq; Chromatin; Chronic; Chronic Disease; Clinical; Cues; Cyclic GMP; DNA; DNA Damage; DNA Repair; Data Set; Diabetes Mellitus; Disease; Drug or chemical Tissue Distribution; Elderly; Epigenetic Process; Erythroid; Exhibits; Failure; Family; Femur; Fluorescence; Frequencies; Gene Expression; Genes; Goals; Haplotypes; Health; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunobiology; Inflammation; Inflammatory; Innate Immune Response; Interferon Type I; Interferons; Investigation; Link; Liver; Longevity; Longitudinal Studies; Lung; Malignant Neoplasms; Maps; Mediating; Metabolic; Metabolic Diseases; Molecular; Mus; Myelogenous; Nucleic Acids; Organism; Participant; Pathologic; Pathway interactions; Patients; Pattern; Peritoneum; Phenotype; Population; Process; Production; RNA; Radiation therapy; Reporter; Reporting; Resolution; Role; S100 Proteins; Shapes; Signal Transduction; Signaling Molecule; Spleen; Stimulator of Interferon Genes; Stimulus; Testing; Tissues; Work; age related; aged; cohort; cytokine; defined contribution; epigenome; gene network; genetic signature; genome-wide; human subject; immune function; immunomodulatory strategy; innate immune pathways; innovation; loss of function; macrophage; next generation sequencing; novel; progenitor; public health relevance; recruit; sensor; therapeutic target; tissue repair; transcriptome; transcriptome sequencing; tumorigenesis; volunteer; young adult

Chronic inflammation is a common pathological basis for age-associated increases in autoimmunity, diabetes, cancer, cardiovascular and Alzheimer’s disease as well as shortened lifespan. Failure to resolve an activated innate immune response contributes significantly to chronic inflammation. Despite the profound clinical implications, the specific innate pathways contributing to chronic inflammation remain unknown. We reasoned that age-associated accrual of damaged DNA, which in other settings is a known driver of inflammation through cell-intrinsic DNA-sensing pathways, may contribute to age-associated chronic inflammation through these same innate pathways. Notably, cell-intrinsic DNA-sensing pathways require the participation of the DNA-sensor, cGAS and ER-resident adaptor, STING and are potent inducers of the pleiotropic cytokine family, type I interferons (IFN-I). IFN-I have been linked to chronic inflammation in disorders such as autoimmunity and cancer. While the molecular components of age-associated chronic inflammation remain undefined, a significant body of work suggests that recirculating innate cells may be compromised, however, the contribution of tissue resident macrophages to aging has not been addressed. Tissue macrophages are distinct from other myeloid-derived cells, not only in their origins, but also because they integrate epigenetic and microenvironment cues to carry out a unique set of functions. In addition to mounting innate immune responses, tissue macrophages are indispensable for tissue patterning, resolution of inflammation and tissue repair. Here we propose to test the hypothesis that cytosolic DNA-sensing promotes constitutive IFN-I induction within tissue macrophages and drives age-associated chronic inflammation. We will systematically address how specific innate processes contribute to immune dysfunction in the elderly in three specific aims. 1) We will evaluate the contribution of cytosolic DNA-sensing pathways to aging-associated constitutive IFN-I and proinflammatory signatures in tissues and resident macrophages using mice deficient in cGAS and STING. 2) We will determine the direct contribution cytosolic DNA sensing pathways in exclusively shaping tissue macrophage fate and function with age by conditionally deleting STING directly in tissue macrophage progenitors. As the epigenomes and transcriptomes of tissue macrophages are highly plastic, we will utilize next generation sequencing to identify genome-wide changes instigated by cytosolic DNA-sensing pathways in these cells with progressive age. 3) Finally, we will extend our findings to humans and determine the baseline IFN-I signatures and responsiveness of tissue macrophages from the lungs of geriatric patients and correlate them to well-represented loss-of-function haplotypes of STING. By uncovering the molecular details of chronic inflammation in aging humans, the findings from this study offer new immunomodulatory strategies and targets to bolster protective immunity as well as block detrimental inflammation, as desired, during aging.

慢性炎症是自身免疫性增加的常见病理基础， 糖尿病，癌症，心血管和阿尔茨海默氏病以及寿命缩短。无法解决 活化的先天免疫反应对慢性炎症产生了重大贡献。尽管有深刻的态度 临床意义，导致慢性炎症的特定先天途径尚不清楚。我们 理由认为，与年龄相关的受损DNA的辅助是在其他情况下是已知的驱动因素 通过细胞中性DNA感应途径的炎症可能有助于与年龄相关的慢性 通过这些先天途径的炎症。值得注意的是，细胞中的DNA感应途径需要 DNA传感器，CGA和ER居民适配器的参与，Sting，并且是潜在的诱导剂 多效性细胞因子家族，I型干扰素（IFN-I）。 IFN-I与慢性炎症有关 自身免疫和癌症等疾病。而年龄相关的慢性分子成分 炎症仍然不确定，大量的工作表明，循环先天细胞可能是 然而，尚未解决组织居民巨噬细胞对衰老的贡献。 组织巨噬细胞不仅与其他髓样细胞不同，不仅在其起源，而且还因为 他们集成了表观遗传和微环境提示，以执行独特的功能。此外 安装先天免疫反应，组织巨噬细胞对于组织模式，分辨率是必不可少的 炎症和组织修复。在这里，我们建议测试胞质DNA传感的假设 促进组织巨噬细胞中的本构IFN-I诱导，并驱动与年龄相关的慢性 炎。我们将系统地解决特定的先天过程如何促进免疫 在三个特定目的中，恢复功能障碍。 1）我们将评估胞质DNA感应的贡献 在组织和居民中与衰老相关的IFN-I和促炎的特征的途径 巨噬细胞使用CGA和STING缺乏的小鼠。 2）我们将确定直接贡献的胞质 DNA敏感性途径专门塑造组织巨噬细胞命运，并通过条件地与年龄发挥作用 直接在组织巨噬细胞祖细胞中删除刺。作为组织的表观人工学和转录组 巨噬细胞是高度塑料的，我们将利用下一代测序来识别全基因组的变化 在这些具有渐进式年龄的细胞中，通过胞质DNA传感途径促进。 3）最后，我们将扩展我们的 对人类的发现，并确定组织巨噬细胞的基线IFN-I特征和反应性 从老年患者的肺部，将它们与刺激的功能丧失单倍型相关。 通过发现衰老人类慢性感染的分子细节，这项研究的发现提出了 新的免疫调节策略和目标，以增强受保护的免疫力以及确定块 衰老期间，炎症，根据需要。