Innate Immunity in NASH

NASH 中的先天免疫

• 批准号: 10720481
• 负责人: Juli Bai
• 金额: $ 47.4万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720481
• 关键词: Adipocytes; Apoptosis; Apoptotic; Binding; Biology; Cell Death; Cell membrane; Cells; Cessation of life; Chronic; Cyclic GMP; DNA; DNA Binding; Development; Diet; Disease; Ectopic Expression; Equilibrium; Event; Fibrosis; Goals; Guanosine Triphosphate; Hepatocyte; Homeostasis; Immune; Immune signaling; Impairment; In Vitro; Inflammation; Innate Immune System; Insulin Resistance; Knock-out; Kupffer Cells; Link; Liver; Liver Fibrosis; Liver diseases; Macrophage; Mediating; Membrane; Metabolic Diseases; Molecular; Mus; Natural Immunity; Nature; Organ; Outcome; Pathogenesis; Pathologic; Pathway interactions; Phagocytes; Phagocytosis; Phagocytosis Induction; Phagosomes; Pharmaceutical Preparations; Phase; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Physiological; Play; Population; Primary carcinoma of the liver cells; Regulation; Rest; Role; SYK gene; Signal Transduction; Stimulator of Interferon Genes; Testing; Therapeutic; Thinking; Tissues; cell injury; chemokine; cytokine; diet-induced obesity; ds-DNA; end stage liver disease; enzyme activity; epidemiology study; immune activation; immunoregulation; improved; in vivo; injured; innate immune pathways; innate immune sensing; liver inflammation; monocyte; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; prevent; protective pathway; recruit; sensor; spatiotemporal; therapeutically effective; tissue injury

Nonalcoholic steatohepatitis (NASH), a cell death and inflammation-associated nonalcoholic fatty liver disease (NAFLD), is the leading cause of hepatocellular carcinoma (HCC) and end-stage liver failure worldwide. There is no effective therapeutic drug for NASH to date, highlighting an urgent need for the identification of novel targets for this devastating disease. Evidence cumulated over the past decade strongly suggest that the innate immune system, specifically the liver-resident macrophages (Kupffer cells) and recruited monocyte-derived macrophages, play a key role in NASH progression and pathogenesis. The current study aims to elucidate the mechanisms by which macrophage cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates liver fibrosis and NASH pathogenesis. We found that macrophage-specific knockout of cGAS or STING promotes liver inflammation, apoptosis, and fibrosis, suggesting this DNA sensing innate immune pathway protects, rather than promotes, NASH progression in mice. However, how cGAS or STING deficiency leads to NASH pathogenesis remains unknown. Our preliminary study suggests that macrophage cGAS may suppress NASH development by facilitating macrophage phagocytosis via both STING-dependent and independent novel mechanisms. To test this hypothesis, we will 1) delineate the STING-independent molecular mechanism by which cGAS promotes macrophages phagocytosis; 2) Elucidate the STING-dependent signaling mechanism by which cGAS regulates macrophage phagocytosis; and 3) Explore the physiological role of cGAS-regulated phagocytosis in preventing liver fibrosis and NASH. Our study will dissect a novel role mechanism by which cGAS regulates macrophage phagocytosis and prevents NASH. The comprehensive understanding of the fundamental functions of the innate immunity and macrophage biology will not only provide a proof-of-concept for rethinking the nature of this devastating liver disease, but also open a new therapeutic avenue for developing therapeutic treatment of NASH.

非酒精性脂肪性肝炎（NASH），一种细胞死亡和炎症相关的非酒精性脂肪性肝病 非酒精性脂肪肝（NAFLD）是全球范围内肝细胞癌（HCC）和终末期肝衰竭的主要原因。有 迄今为止，尚无有效的NASH治疗药物，这突出表明迫切需要确定新的靶点 这种毁灭性的疾病。过去十年累积的证据强烈表明，先天免疫 系统，特别是肝脏驻留的巨噬细胞（枯否细胞）和募集的单核细胞衍生的 巨噬细胞在NASH进展和发病机制中起关键作用。本研究旨在阐明 巨噬细胞环GMP-AMP合酶（cGAS）-干扰素基因刺激因子（STING） 途径调节肝纤维化和NASH发病机制。我们发现巨噬细胞特异性敲除cGAS 或STING促进肝脏炎症、凋亡和纤维化，表明这种DNA传感先天免疫 在小鼠中，NASH通路保护而不是促进NASH进展。然而，cGAS或STING缺陷 导致NASH的发病机制尚不清楚。我们的初步研究表明，巨噬细胞cGAS可能 通过促进巨噬细胞吞噬作用抑制NASH发展， 独立的新机制。为了验证这一假设，我们将1）描述STING独立的分子 cGAS促进巨噬细胞吞噬作用的机制; 2）阐明STING依赖性信号传导 cGAS调节巨噬细胞吞噬作用的机制;以及3）探索cGAS的生理作用。 cGAS调节的吞噬作用预防肝纤维化和NASH。我们的研究将剖析一个新的角色 cGAS调节巨噬细胞吞噬作用并预防NASH的机制。综合 了解先天免疫和巨噬细胞生物学的基本功能， 重新思考这种毁灭性肝病的性质的概念验证，同时也开辟了一种新的治疗方法， 开发NASH治疗性治疗的途径。