Free cholesterol accumulation in macrophage membranes activates Toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K
Authors
Sun, YuIshibashi, Minako
Seimon, Tracie
Lee, Mingsum
Sharma, Sudarshana M.
Fitzgerald, Katherine A.
Samokhin, Andriy O.
Wang, Yibin
Sayers, Scott
Aikawa, Masanori
Jerome, W. Gray
Ostrowski, Michael C.
Bromme, Dieter
Libby, Peter
Tabas, Ira A.
Welch, Carrie L.
Tall, Alan R.
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2009-01-06Keywords
Adaptor Proteins, Vesicular TransportAnimals
Aorta
Apolipoproteins E
Cathepsin K
Cathepsins
Cell Membrane
Cells, Cultured
Cholesterol
E-Box Elements
Endosomes
Enzyme Induction
Humans
Macrophages
Matrix Metalloproteinase 14
Matrix Metalloproteinase 8
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Microphthalmia-Associated Transcription Factor
Phosphorylation
Promoter Regions, Genetic
Proteins
Receptor Activator of Nuclear Factor-kappa B
S100 Proteins
*Signal Transduction
Time Factors
Toll-Like Receptor 3
Toll-Like Receptor 4
p38 Mitogen-Activated Protein Kinases
rab GTP-Binding Proteins
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
The molecular events linking lipid accumulation in atherosclerotic plaques to complications such as aneurysm formation and plaque disruption are poorly understood. BALB/c-Apoe(-/-) mice bearing a null mutation in the Npc1 gene display prominent medial erosion and atherothrombosis, whereas their macrophages accumulate free cholesterol in late endosomes and show increased cathepsin K (Ctsk) expression. We now show increased cathepsin K immunostaining and increased cysteinyl proteinase activity using near infrared fluorescence imaging over proximal aortas of Apoe(-/-), Npc1(-/-) mice. In mechanistic studies, cholesterol loading of macrophage plasma membranes (cyclodextrin-cholesterol) or endosomal system (AcLDL+U18666A or Npc1 null mutation) activated Toll-like receptor (TLR) signaling, leading to sustained phosphorylation of p38 mitogen-activated protein kinase and induction of p38 targets, including Ctsk, S100a8, Mmp8, and Mmp14. Studies in macrophages from knockout mice showed major roles for TLR4, following plasma membrane cholesterol loading, and for TLR3, after late endosomal loading. TLR signaling via p38 led to phosphorylation and activation of the transcription factor Microphthalmia transcription factor, acting at E-box elements in the Ctsk promoter. These studies suggest that free cholesterol enrichment of either plasma or endosomal membranes in macrophages leads to activation of signaling via various TLRs, prolonged p38 mitogen-activated protein kinase activation, and induction of Mmps, Ctsk, and S100a8, potentially contributing to plaque complications.Source
Circ Res. 2009 Feb 27;104(4):455-65. Epub 2009 Jan 2. Link to article on publisher's siteDOI
10.1161/CIRCRESAHA.108.182568Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35223PubMed ID
19122179Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1161/CIRCRESAHA.108.182568
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