2. Academic Validation
  3. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis

Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis

  • Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2107682118. doi: 10.1073/pnas.2107682118.
Xinbo Zhang 1 2,  Jeffrey G McDonald 3 4,  Binod Aryal 1 2,  Alberto Canfrán-Duque 1 2,  Emily L Goldberg 2 5,  Elisa Araldi 6,  Wen Ding 1 2,  Yuhua Fan 1 2,  Bonne M Thompson 3 4,  Abhishek K Singh 1 2,  Qian Li 7,  George Tellides 1 8,  Jose Ordovás-Montanes 9 10,  Rolando García Milian 11,  Vishwa Deep Dixit 1 4,  Elina Ikonen 12 13,  Yajaira Suárez 14 15 2,  Carlos Fernández-Hernando 14 15 2
Affiliations

Affiliations

  • 1 Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520.
  • 2 Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520.
  • 3 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 4 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
  • 5 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
  • 6 Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology Zurich, Schwerzenbach CH-8603, Switzerland.
  • 7 Department of Neuroscience and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06520.
  • 8 Department of Surgery, Yale University School of Medicine, New Haven, CT 06520.
  • 9 Broad Institute of MIT and Harvard, Cambridge, MA 02115.
  • 10 Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
  • 11 Bioinformatics Support Program, Yale University School of Medicine, New Haven, CT 06520.
  • 12 Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland; carlos.fernandez@yale.edu yajaira.suarez@yale.edu elina.ikonen@helsinki.fi.
  • 13 Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland.
  • 14 Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520; carlos.fernandez@yale.edu yajaira.suarez@yale.edu elina.ikonen@helsinki.fi.
  • 15 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520.
PMID: 34782454 DOI: 10.1073/pnas.2107682118
Abstract

Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant Cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating Cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the Enzyme that catalyzes conversion of desmosterol to Cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial Reactive Oxygen Species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage Cholesterol metabolism and inflammatory activation and protecting from disease progression.

Keywords

atherosclerosis; cholesterol; immunometabolism; macrophages.

Figures
Products