Figure 2. Sites of interaction between RCT and TLRs in the macrophage.
ABCA1 null macrophages have an enhanced pro-inflammatory response to ligands for TLR2, TLR4, TLR7, and TLR9 compared with wt macrophages, likely reflecting increased cholesterol and TLR assembly in lipid rafts. ABCG1 null macrophages have a similar TLR-hyperresponsive phenotype. Conversely, apoA-I suppresses cytokine induction through an ABCA1-activated JAK2-STAT3 pathway and perhaps also through disrupting rafts, while HDL suppresses the type I interferon response pathway downstream of TLR4, by promoting translocation of the TLR adaptor TRAM to intracellular compartments. SR-BI also suppresses TLR4-mediated NF-κB activation. Pathogens in turn interfere with LXR signaling by stimulating TLR3/4-dependent activation of IRF-3, which is thought to interact with the LXRE on LXR target genes, such ABCA1 and ABCG1. HDL and apoA-I can also activate the ectodomain shedding of ADAM17 substrates, such as TNFR2, TNFR1, and TNFα, leading to their release.
ABC, ATP binding cassette; Adam, a disintegrin and metalloproteinase; HDL, high density lipoprotein; IRF, interferon regulatory factor; Jak, Janus kinase; LXR, Liver X Receptor; SR-BI, scavenger receptor class B type I; Stat3, signal transducer and activator of transcription; TLR, Toll like Receptor; TNFR, tumor necrosis factor receptor.