John Owen - Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol.

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      Publication Details (including relevant citation   information):

      J Lipid Res 51:3196-3206, 2010

      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.

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