Lysosomal cholesterol hydrolysis couples efferocytosis to anti-inflammatory oxysterol production

Manon Viaud, Stoyan Ivanov, Nemanja Vujic, Madalina Duta-Mare, Lazaro Emilio Aira, Thibault Barouillet, Elsa Garcia, Francois Orange, Isabelle Dugail, Isabelle Hainault, Christian Stehlik, Sandrine Marchetti, Laurent Boyer, Rodolphe Guinamard, Fabienne Foufelle, Andrea Bochem, Kees G. Hovingh, Edward B. Thorp, Emmanuel L. Gautier, Dagmar KratkyPaul Dasilva-Jardine, Laurent Yvan-Charvet*

*Corresponding author for this work

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1369-1384
Number of pages16
JournalCirculation research
Volume122
Issue number10
DOIs
StatePublished - May 2018

Keywords

  • Cholesterol
  • Inflammation
  • Macrophage
  • Mitochondria
  • Oxysterols

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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