Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol
Lipopolysaccharides
lymphocytes
0301 basic medicine
retinoids
free cholesterol
lipid droplets
APOA-I
Activation
Expression
QD415-436
Biochemistry
INNATE IMMUNE RECOGNITION
immunology
Mice
03 medical and health sciences
Membrane Microdomains
Accumulation
Animals
ABCA1-DEFICIENT MACROPHAGES
Inflammation
Macrophages
Toll-Like Receptors
NF-kappa B
TANGIER-DISEASE
cytokines
Mice, Inbred C57BL
Toll-Like Receptor 4
Protein Transport
Cholesterol
ATHEROSCLEROSIS
Toll-Like Receptor 9
Myeloid Differentiation Factor 88
PLASMA-MEMBRANE
ATP-Binding Cassette Transporters
CASSETTE TRANSPORTER A1
Gene Deletion
ATP Binding Cassette Transporter 1
Signal Transduction
DOI:
10.1194/jlr.m006486
Publication Date:
2010-07-23T00:37:52Z
AUTHORS (9)
ABSTRACT
We previously showed that macrophages from macrophage-specifi c ATP-binding cassette transporter A1 (ABCA1) knockout (Abca1(-M/-M)) mice had an enhanced proinflammatory response to the Toll-like receptor (TLR) 4 agonist, lipopolysaccharide (LPS), compared with wild-type (WT) mice. In the present study, we demonstrate a direct association between free cholesterol (FC), lipid raft content, and hyper-responsiveness of macrophages to LPS in WT mice. Abca1(-M/-M) macrophages were also hyper-responsive to specific agonists to TLR2, TLR7, and TLR9, but not TLR3, compared with WT macrophages. We hypothesized that ABCA1 regulates macrophage responsiveness to TLR agonists by modulation of lipid raft cholesterol and TLR mobilization to lipid rafts. We demonstrated that Abca1(-M/-M) vs. WT macrophages contained 23% more FC in isolated lipid rafts. Further, mass spectrometric analysis suggested raft phospholipid composition was unchanged. Although cell surface expression of TLR4 was similar between Abca1(-M/-M) and WT macrophages, significantly more TLR4 was distributed in membrane lipid rafts in Abca1(-M/-M) macrophages. Abca1(-M/-M) macrophages also exhibited increased trafficking of the predominantly intracellular TLR9 into lipid rafts in response to TLR9-specifi c agonist (CpG). Collectively, our data suggest that macrophage ABCA1 dampens inflammation by reducing MyD88-dependent TLRs trafficking to lipid rafts by selective reduction of FC content in lipid rafts.
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