Olivier Govaere1, Sine Kragh Petersen2, Nuria Martinez-Lopez3, Jasper Wouters4, Matthias Van Haele5, Rosellina M Mancina6, Oveis Jamialahmadi6, Orsolya Bilkei-Gorzo2, Pierre Bel Lassen7, Rebecca Darlay8, Julien Peltier9, Jeremy M Palmer10, Ramy Younes11, Dina Tiniakos12, Guruprasad P Aithal13, Michael Allison14, Michele Vacca15, Melker Göransson16, Rolando Berlinguer-Palmini17, James E Clark10, Michael J Drinnan10, Hannele Yki-Järvinen18, Jean-Francois Dufour19, Mattias Ekstedt20, Sven Francque21, Salvatore Petta22, Elisabetta Bugianesi23, Jörn M Schattenberg24, Christopher P Day10, Heather J Cordell8, Baki Topal25, Karine Clément7, Stefano Romeo6, Vlad Ratziu26, Tania Roskams5, Ann K Daly10, Quentin M Anstee27, Matthias Trost28, Anetta Härtlova29. 1. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: olivier.govaere@newcastle.ac.uk. 2. Wallenberg Centre for Molecular and Translational Medicine, Department of Microbiology and Immunology at Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. 3. 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. 4. Center for Brain & Disease Research, VIB-KU Leuven, Leuven, Belgium; Department of Human Genetics, KU Leuven, Leuven, Belgium. 5. Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven, Leuven, Belgium. 6. The Wallenberg Laboratory for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden. 7. Nutrition and obesity: systemic approaches, Inserm, Sorbonne University, Paris, France. 8. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 9. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 10. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 11. 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. 12. 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. 13. NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom. 14. Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University NHS Foundation Trust, United Kingdom. 15. University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom. 16. Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 17. Bioimaging Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 18. Minerva Foundation Institute for Medical Research and Department of Medicine, University of Helsinki, Helsinki, Finland. 19. University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland; Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland. 20. Division of Gastroenterology and Hepatology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden. 21. Department of Gastroenterology and Hepatology, Antwerp University Hospital & University of Antwerp, Antwerp, Belgium. 22. Sezione di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Palermo, Italy. 23. Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy. 24. I. Department of Medicine, University Hospital Mainz, Mainz, Germany. 25. Department of Abdominal Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium. 26. Assistance Publique-Hôpitaux de Paris, hôpital Beaujon, University Paris-Diderot, Paris, France. 27. 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. Electronic address: quentin.anstee@newcastle.ac.uk. 28. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: matthias.trost@newcastle.ac.uk. 29. 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. Electronic address: anetta.hartlova@gu.se.
Abstract
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.
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.
Authors: George A E Pickering; Favour Felix-Ilemhenbhio; Matthew J Clark; Klaudia Kocsy; Jonathan Simpson; Ilaria Bellantuono; Alison Gartland; Jeremy Mark Wilkinson; Konstantinos Hatzikotoulas; Endre Kiss-Toth Journal: Int J Mol Sci Date: 2022-08-16 Impact factor: 6.208