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Circ Res. 2018 May 11;122(10):1369-1384. doi: 10.1161/CIRCRESAHA.117.312333. Epub 2018 Mar 9.

Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production.

Author information

1
From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France (M.V., S.I., L.-E.A., E.G., S.M., L.B., R.G., L.Y.-C.).
2
Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria (N.V., M.D.-M., D.K.).
3
Acquire Innovation Ltd, Dublin, Ireland (T.B.).
4
UFR Sciences, Faculté des Sciences de l'Université de Nice-Sophia Antipolis, France (F.O.).
5
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Pierre & Marie Curie University, ICAN Institute of Cardiometabolism & Nutrition, Hôpital de la Pitié, Boulevard de l'Hôpital, Paris, France (I.D., E.L.G.).
6
Institut National de la Santé et de la Recherche Médicale (Inserm) UMRS 1138, Centre de Recherche des Cordeliers, Paris, France (I.H., F.F.).
7
Department of Pathology, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL (C.S., E.B.T.).
8
Cardiology (A.B.).
9
Department of Vascular Medicine (K.G.H.).
10
Academic Medical Center, Amsterdam, The Netherlands; and Staten Biotechnology, Nijmegen, The Netherlands (P.D.-J.).
11
From the Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France (M.V., S.I., L.-E.A., E.G., S.M., L.B., R.G., L.Y.-C.) yvancharvet@unice.fr.

Abstract

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.

KEYWORDS:

cholesterol; inflammation; macrophage; mitochondria; oxysterols

PMID:
29523554
PMCID:
PMC6034181
[Available on 2019-05-11]
DOI:
10.1161/CIRCRESAHA.117.312333

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