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
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (46)
CITATIONS (288)