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LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.
- Source :
- Cell Reports; May2024, Vol. 43 Issue 5, pN.PAG-N.PAG, 1p
- Publication Year :
- 2024
-
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<superscript>+</superscript>) depletion in macrophages. Cholesterol-mediated NAD<superscript>+</superscript> depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD<superscript>+</superscript> 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<superscript>+</superscript> deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration. [Display omitted] • Cholesterol promotes macrophage senescence by NAD<superscript>+</superscript> depletion via LXR/CD38 signaling • Senescent macrophages accumulate in the subretinal space in AMD model mice • NAD<superscript>+</superscript> augmentation and senolytics can suppress subretinal drusenoid deposits • Cell-mediated clearance has the capacity to remove subretinal deposits Terao et al. demonstrated how dysregulated cholesterol metabolism drives macrophage senescence and the development of subretinal drusenoid deposits in mice. LXR/CD38 signaling activated by cholesterol reduces NAD<superscript>+</superscript> availability and promotes macrophage senescence. Senolytic agents targeting NAD<superscript>+</superscript> decline and senescent macrophages are a potential therapeutic option against early AMD. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 26391856
- Volume :
- 43
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- 177420969
- Full Text :
- https://doi.org/10.1016/j.celrep.2024.114102