Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease,Journal of Hepatology

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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-12-21 , DOI: 10.1016/j.jhep.2021.12.012
Olivier Govaere ₁ , Sine Kragh Petersen ₂ , Nuria Martinez-Lopez ₃ , Jasper Wouters ₄ , Matthias Van Haele ₅ , Rosellina M Mancina ₆ , Oveis Jamialahmadi ₆ , Orsolya Bilkei-Gorzo ₂ , Pierre Bel Lassen ₇ , Rebecca Darlay ₈ , Julien Peltier ₉ , Jeremy M Palmer ₁ , Ramy Younes ₁₀ , Dina Tiniakos ₁₁ , Guruprasad P Aithal ₁₂ , Michael Allison ₁₃ , Michele Vacca ₁₄ , Melker Göransson ₁₅ , Rolando Berlinguer-Palmini ₁₆ , James E Clark ₁ , Michael J Drinnan ₁ , Hannele Yki-Järvinen ₁₇ , Jean-Francois Dufour ₁₈ , Mattias Ekstedt ₁₉ , Sven Francque ₂₀ , Salvatore Petta ₂₁ , Elisabetta Bugianesi ₂₂ , Jörn M Schattenberg ₂₃ , Christopher P Day ₁ , Heather J Cordell ₈ , Baki Topal ₂₄ , Karine Clément ₇ , Stefano Romeo ₆ , Vlad Ratziu ₂₅ , Tania Roskams ₅ , Ann K Daly ₁ , Quentin M Anstee ₂₆ , Matthias Trost ₉ , Anetta Härtlova ₂₇

Affiliation

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Wallenberg Centre for Molecular and Translational Medicine, Department of Microbiology and Immunology at Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Center for Brain & Disease Research, VIB-KU Leuven, Leuven, Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium.
Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
The Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
Nutrition and obesity: systemic approaches, Inserm, Sorbonne University, Paris, France.
Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Pathology, Aretaieio Hospital, National & Kapodistrian University of Athens, Athens, Greece.
NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.
Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom.
University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Bioimaging Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Minerva Foundation Institute for Medical Research and Department of Medicine, University of Helsinki, Helsinki, Finland.
University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland; Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland.
Division of Gastroenterology and Hepatology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
Department of Gastroenterology and Hepatology, Antwerp University Hospital & University of Antwerp, Antwerp, Belgium.
Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Palermo, Italy.
Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
I. Department of Medicine, University Hospital Mainz, Mainz, Germany.
Department of Abdominal Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
Assistance Publique-Hôpitaux de Paris, hôpital Beaujon, University Paris-Diderot, Paris, France.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom.
Wallenberg Centre for Molecular and Translational Medicine, Department of Microbiology and Immunology at Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background & Aims

Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood.

Methods

A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1^-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank.

Results

MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients.

Conclusions

Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD.

Lay summary

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice.

中文翻译：

巨噬细胞清道夫受体 1 介导非酒精性脂肪性肝病中脂质诱导的炎症

背景与目标

肥胖相关炎症是非酒精性脂肪性肝病 (NAFLD) 发病机制的关键因素。然而，巨噬细胞清道夫受体 1 (MSR1, CD204) 的作用仍不完全清楚。

方法

共处理了 170 份 NAFLD 肝活检以进行转录组学分析，并与临床病理学特征相关联。Msr1 ^-/-和野生型小鼠接受了 16 周的高脂肪和高胆固醇饮食。用针对 MSR1 的单克隆抗体处理小鼠和离体人肝切片。使用来自 1,483 名 NAFLD 患者和 430,101 名英国生物银行参与者的全基因组关联研究数据评估遗传易感性。

结果

MSR1 表达与肝脏载脂泡沫巨噬细胞的发生有关，并与 NAFLD 患者的脂肪变性和脂肪性肝炎程度相关。缺乏 Msr1 的小鼠免受饮食诱导的代谢紊乱，表现出较少的肝脏泡沫巨噬细胞、较少的肝脏炎症、改善的血脂异常和葡萄糖耐量以及肝脏脂质代谢的改变。在饱和脂肪酸的诱导下，MSR1 通过 JNK 信号通路诱导促炎反应。体外受体的阻断阻止了原代巨噬细胞中脂质的积累，从而抑制了向促炎表型的转变和细胞因子如 TNF-ɑ 的释放。在肥胖相关的 NAFLD 小鼠模型和人肝切片中使用单克隆抗体治疗靶向 MSR1 可防止泡沫巨噬细胞形成和炎症。此外，我们发现 rs41505344 是MSR1上游转录区的多态性，在超过 400,000 名患者的队列中与血清甘油三酯和天冬氨酸氨基转移酶水平的改变有关。