NASH-associated macrophages: regulation and role in disease pathogenesis

项目总结/摘要 肥胖症的流行增加了非酒精性脂肪肝的患病率， 临床良性肝脂肪变性至非酒精性脂肪性肝炎（NASH）。后者代表了更严重的 以存在慢性肝损伤、炎症和肝纤维化为特征的疾病状态， 终末期肝病的风险，如肝硬化和肝细胞癌（HCC）。宏观戏剧 在宿主防御、组织稳态和疾病进展中起着不可或缺的作用。改变的巨噬细胞 极化，其特点是在其转录和功能状态的变化，已被因果联系， 包括NASH在内的代谢性疾病的发病机制。尽管如此，巨噬细胞异质性的本质， 疾病相关的重编程，其对NASH进展的贡献仍然不清楚。解决 这些挑战，我们最近进行了单细胞RNA测序分析的肝细胞分离， 健康和饮食诱导的NASH小鼠。我们的研究发现了一个独特的人群NASH相关的 巨噬细胞（NAM）与小鼠和人NASH表现出强相关性。几个重要 这些发现中出现了有关触发NAM诱导的病理生理信号的问题，其 在NASH发病机制中的作用及其潜在机制。根据初步数据，我们 假设NASH期间肝内致病性刺激驱动NAM诱导，从而重塑肝脏 微环境和加剧疾病进展。在本提案中，我们计划阐明 促进NAM诱导的途径，并严格评估其在疾病发病机制中的作用。我们计划 探索NAMs促进肝脏微环境重编程的机制。

Project Summary/Abstract The obesity epidemic has increased the prevalence of non-alcoholic fatty liver disease, which ranges from clinically benign hepatic steatosis to non-alcoholic steatohepatitis (NASH). The latter represents a more severe disease state featured by the presence of chronic liver injury, inflammation, and liver fibrosis, which increases the risk for end-stage liver disease such as cirrhosis and hepatocellular carcinoma (HCC). Macrophages play an integral role in host defense, tissue homeostasis, and disease progression. Altered macrophage polarization, characterized by changes in its transcriptional and functional states, has been causally linked to the pathogenesis of metabolic disease including NASH. Despite this, the nature of macrophage heterogeneity, disease-associated reprogramming, and its contribution to NASH progression remains obscure. To address these challenges, we recently performed single-cell RNA sequencing analysis on liver cells isolated from healthy and diet-induced NASH mice. Our study uncovered a unique population of NASH-associated macrophages (NAMs) that exhibits strong association with mouse and human NASH. Several important questions emerge from these findings regarding the pathophysiological signals that trigger NAM induction, its role in NASH pathogenesis, and the underlying mechanisms. Based on a body of preliminary data, we hypothesize that intrahepatic pathogenic stimuli drive NAM induction during NASH, thereby reshaping the liver microenvironment and exacerbating disease progression. In this proposal, we plan to elucidate the signaling pathways that promote NAM induction and critically assess its role in disease pathogenesis. We plan to explore the mechanisms through which NAMs contribute to the reprogramming of the liver microenvironment.