LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion

Ryo Terao; Tae Jun Lee; Jason Colasanti; Charles W Pfeifer; Joseph B Lin; Andrea Santeford; Keitaro Hase; Shinobu Yamaguchi; Daniel Du; Brian S Sohn; Yo Sasaki; Mitsukuni Yoshida; Rajendra S Apte

doi:10.1016/j.celrep.2024.114102

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD⁺ depletion

Cell Rep. 2024 Apr 15:114102. doi: 10.1016/j.celrep.2024.114102. Online ahead of print.

Authors

Affiliations

¹ John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
² John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
³ John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
⁴ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁵ John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: mitsukuni@wustl.edu.
⁶ John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: apte@wustl.edu.

PMID: 38636518
DOI: 10.1016/j.celrep.2024.114102

Abstract

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD⁺) depletion in macrophages. Cholesterol-mediated NAD⁺ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD⁺ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD⁺ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Keywords: CD38; CP: Immunology; CP: Metabolism; NAD(+); NMN; age-related macular degeneration; cellular senescence; cholesterol efflux; neurodegeneration; nicotinamide adenine dinucleotide; nicotinamide mononucleotide.