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

基本信息

批准号：
10551296
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
项目类别：
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/10551296
关键词：
Address Adipose tissue Adult Affect Age Aging Alleles Alzheimer&apos s Disease Animals Architecture Attenuated Autoimmune Diseases Autoimmunity Autologous Biology Brain Cardiovascular Diseases Cardiovascular system Cells ChIP-seq Chromatin Chromosome Mapping Chronic Chronic Disease Clinical Communicable Diseases 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 Knockout Mice Link Liver Longevity Lung Macrophage Malignant Neoplasms Mediating 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 analysis human subject immune function immunomodulatory strategy innate immune pathways innovation loss of function nervous system disorder next generation sequencing novel progenitor public health relevance recruit sensor therapeutic target tissue repair transcriptome transcriptome sequencing tumorigenesis volunteer young adult

项目摘要

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.

慢性炎症是与年龄相关的自身免疫增加的常见病理基础，糖尿病、癌症、心血管病和阿尔茨海默病以及寿命缩短未能解决。尽管影响深远，但激活的先天免疫反应对慢性炎症有显着影响。临床意义，慢性炎症的具体先天影响途径仍然未知。推断与年龄相关的受损 DNA 的累积，在其他情况下是已知的驱动因素通过细胞内在 DNA 传感途径产生的炎症可能导致与年龄相关的慢性值得注意的是，细胞内在 DNA 传感途径需要 DNA 传感器、cGAS 和 ER 驻留接头 STING 的参与，并且是多效细胞因子家族 I 型干扰素 (IFN-I) 与慢性炎症有关。自身免疫性疾病和癌症等疾病的分子成分与年龄相关。炎症仍未明确，大量研究表明再循环的先天细胞可能是然而，组织驻留巨噬细胞对衰老的影响尚未得到解决。组织巨噬细胞与其他骨髓来源的细胞不同，不仅在于它们的起源，还因为它们整合表观遗传和微环境线索来执行一系列独特的功能。增强先天免疫反应，组织巨噬细胞对于组织模式、分辨率是不可或缺的在这里，我们建议检验细胞质 DNA 传感的假设。促进组织巨噬细胞内的 IFN-I 诱导，并驱动与年龄相关的慢性我们将系统地探讨特定的先天过程如何促进免疫。老年人功能障碍的三个具体目标 1) 我们将评估细胞质 DNA 传感的贡献。组织和居民中与衰老相关的组成型 IFN-I 和促炎特征的途径使用缺乏 cGAS 和 STING 的小鼠的巨噬细胞 2) 我们将确定胞质的直接贡献。 DNA传感途径有条件地随年龄专门塑造组织巨噬细胞的命运和功能直接删除组织巨噬细胞祖细胞中的 STING 作为组织的表观基因组和转录组。巨噬细胞具有高度可塑性，我们将利用下一代测序来识别全基因组变化随着年龄的增长，这些细胞中的胞质 DNA 传感途径会引发 3) 最后，我们将扩展我们的研究。对人类的研究结果并确定组织巨噬细胞的基线 IFN-I 特征和反应性来自老年患者肺部的样本，并将其与具有代表性的 STING 功能丧失单倍型相关联。通过揭示老年人慢性炎症的分子细节，这项研究的结果提供了新的免疫调节策略和目标，以增强保护性免疫力并阻止痛苦根据需要，在衰老过程中发生炎症。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STING promotes homeostatic maintenance of tissues and confers longevity with aging.

STING 促进组织的稳态维持，并随着年龄的增长而延长寿命。

DOI：
10.1101/2024.04.04.588107
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Hopkins,JacobW;Sulka,KatherineB;Sawden,Machlan;Carroll,KimberlyA;Brown,RonaldD;Bunnell,StephenC;Poltorak,Alexander;Tai,Albert;Reed,EricR;Sharma,Shruti
通讯作者：
Sharma,Shruti