Faculty Collaboration Database

Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J Lipid Res 2010 Nov;51(11):3196-206

Date

07/24/2010

Pubmed ID

20650929

Pubmed Central ID

PMC2952560

DOI

10.1194/jlr.M006486

Scopus ID

2-s2.0-78149355932 (requires institutional sign-in at Scopus site)   296 Citations

Abstract

We previously showed that macrophages from macrophage-specific 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-specific 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.

Author List

Zhu X, Owen JS, Wilson MD, Li H, Griffiths GL, Thomas MJ, Hiltbold EM, Fessler MB, Parks JS

MESH terms used to index this publication - Major topics in bold

ATP Binding Cassette Transporter 1
ATP-Binding Cassette Transporters
Animals
Cholesterol
Gene Deletion
Inflammation
Lipopolysaccharides
Macrophages
Membrane Microdomains
Mice
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
NF-kappa B
Protein Transport
Signal Transduction
Toll-Like Receptor 4
Toll-Like Receptor 9
Toll-Like Receptors