Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production
| Autor: | Isabelle Dugail, Nemanja Vujic, Paul Dasilva-Jardine, Andrea E. Bochem, Kees Hovingh, Emmanuel L. Gautier, Fabienne Foufelle, Thibault Barouillet, François Orange, Madalina Duta-Mare, Manon Viaud, Laurent Yvan-Charvet, Lazaro Emilio Aira, Laurent Boyer, Christian Stehlik, Sandrine Marchetti, Edward B. Thorp, Stoyan Ivanov, Elsa Garcia, Dagmar Kratky, Rodolphe Guinamard, Isabelle Hainault |
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| Přispěvatelé: | Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
rac1 GTP-Binding Protein Erythrocytes Oxysterol Physiology Inflammasomes [SDV]Life Sciences [q-bio] Hypercholesterolemia Inflammation Apoptosis Mitochondrion Article Apoptotic cell clearance 03 medical and health sciences Mice NLR Family Pyrin Domain-Containing 3 Protein medicine Macrophage Animals Lymphocytes Efferocytosis ComputingMilieux_MISCELLANEOUS Caspase Liver X Receptors biology Chemistry Hydrolysis Macrophages Neuropeptides Biological Transport Oxysterols Sterol Esterase Cell biology Mitochondria Mice Inbred C57BL 030104 developmental biology Cholesterol Receptors LDL Splenomegaly biology.protein Cholesterol Esters medicine.symptom Cardiology and Cardiovascular Medicine Lysosomes |
| Zdroj: | Circulation Research Circulation Research, American Heart Association, 2018, 122 (10), pp.1369-1384. ⟨10.1161/circresaha.117.312333⟩ |
| ISSN: | 0009-7330 1524-4571 |
| Popis: | Rationale: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress–induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1–dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor–mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance. |
| Databáze: | OpenAIRE |
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