Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Hongxue Shi, Xiaobo Wang, Christopher Sloas, Brennan Gerlach, Arif Yurdagul Jr., Mary P. Moore, Eui Jung Jung, Faridoddin Mirshahi, Luisa Ronzoni, Arun J. Sanyal, Luca Valenti, Chyuan-Sheng Lin, James Montgomery, Bradley Zinker, Michael Klichinsky, Ira Tabas
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引用次数: 0

Abstract

Hepatocyte apoptosis is a key feature of metabolic dysfunction–associated steatohepatitis (MASH), but the fate of apoptotic hepatocytes in MASH is poorly understood. Here, we explore the hypotheses that clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in MASH because of low expression of the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM4; gene Timd4) by MASH liver macrophages, which then drives liver fibrosis in MASH. We show that apoptotic hepatocytes accumulate in human and experimental MASH, using mice fed the fructose-palmitate-cholesterol (FPC) diet or the high-fat, choline-deficient amino acid–defined (HF-CDAA) diet. Apoptotic hepatocyte accumulation is associated with impaired efferocytosis and loss of TIM4. Administration of neutralizing anti-TIM4 antibodies or genetic deletion of Timd4 in Kupffer cells of FPC and HF-CDAA diet–fed mice decreased efferocytosis by liver macrophages, increased profibrotic activation of collagen-producing hepatic stellate cells (HSCs), and accelerated the progression to fibrotic MASH. Genetic restoration of macrophage Timd4 in FPC and HF-CDAA diet–fed MASH mice or cell therapy with TIM4+ macrophages enhanced apoptotic hepatocyte clearance and decreased HSC activation and liver fibrosis. Studies using an ex vivo macrophage HSC cross-talk model and the HF-CDAA MASH model revealed that inactivation of HSCs by efferocytosing macrophages involved macrophage reprogramming to secrete interleukin-10 (IL-10), which activated the IL-10 receptor on HSCs to dampen their profibrotic activation. These findings reveal a key process in the progression from hepatic steatosis to early MASH fibrosis and identify a mechanism-based therapeutic strategy to prevent fibrotic MASH progression.
肝巨噬细胞tim4介导的efferocytosis受损有助于代谢功能障碍相关脂肪性肝炎的纤维化
肝细胞凋亡是代谢功能障碍相关脂肪性肝炎(MASH)的一个关键特征,但对MASH中凋亡肝细胞的命运知之甚少。在这里,我们探讨了肝巨噬细胞(efferocytosis)对死亡肝细胞的清除在MASH中受损的假设,因为MASH肝巨噬细胞对efferocytosis受体T细胞免疫球蛋白和粘蛋白结构域4 (TIM4;基因Timd4)的低表达,从而驱动MASH中的肝纤维化。我们发现凋亡的肝细胞在人类和实验的MASH中积累,用小鼠喂食果糖-棕榈酸-胆固醇(FPC)饮食或高脂肪,胆碱缺乏氨基酸定义(HF-CDAA)饮食。肝细胞凋亡的积累与efferocytosis受损和TIM4的丢失有关。在FPC和HF-CDAA饮食喂养小鼠的Kupffer细胞中给予中和性抗tim4抗体或基因缺失Timd4可减少肝巨噬细胞的efferocytosis,增加胶原生成肝星状细胞(hsc)的纤维化活化,加速纤维化MASH的进展。在FPC和HF-CDAA饮食喂养的MASH小鼠中,巨噬细胞Timd4的基因修复或TIM4+巨噬细胞的细胞治疗增强了凋亡肝细胞的清除,降低了HSC的活化和肝纤维化。体外巨噬细胞HSC串扰模型和HF-CDAA MASH模型的研究显示,巨噬细胞对HSC的失活涉及巨噬细胞重编程以分泌白细胞介素-10 (IL-10),其激活HSC上的IL-10受体以抑制其纤维化活化。这些发现揭示了从肝脂肪变性到早期MASH纤维化进展的关键过程,并确定了一种基于机制的治疗策略来防止纤维化的MASH进展。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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