HDL regulates type I IFN pathway
MedWire News: A US study shows that high-density lipoprotein (HDL) may control inflammation during infection through suppression of the type I interferon (IFN) response.
Jay Heinecke (University of Washington, USA) and colleagues say that HDL inhibits expression of a subset of lipopolysaccharide (LPS)-induced genes that regulate the type I IFN signaling pathway, independent of sterol metabolism.
"These observations raise the possibility that therapies that raise HDL levels might act in novel ways to retard atherosclerosis, and perhaps other immune disorders," they say.
For the purpose of the study, the team exposed macrophages to mouse HDL and then challenged them with LPS, a microbial ligand for toll-like receptor (TLR)-4.
Microarray analysis showed that HDL inhibited the expression of 30% of genes normally induced by LPS (277 of 911 genes), and this was independent of macrophage cholesterol stores.
Heinecke's team says that the main targets of HDL were the type I IFN signaling pathway and the toll/interleukin-1 receptor (TIR) domain-containing adaptor protein inducing interferon (TRIF)/ TRIF-related adapter molecule (TRAM) signaling pathway, both of which are antiviral immunoregulatory pathways.
Further immunofluorescent analysis suggested that HDL induces the translocation of TRAM into endosomes, or other intracellular compartments, which may reduce subsequent signaling by TLR-4 and TRAM/TRIF.
To investigate whether HDL prevents LPS from inducing TRAM/TRIF genes in vivo, the researchers infected wild type and apolipoprotein A-1 deficient mice with Salmonella typhimurium, a gram-negative bacterium that expresses LPS, and compared the plasma levels of IFN-β, a key regulator of the type I IFN response, and IFN-α, a key regulator of the type II IFN response.
Plasma levels of IFN-β were six-fold higher in apolipoprotein A-1 deficient mice, compared with wild type. In contrast, the two strains of mice had similar levels of TNF-α.
Writing in the journal Circulation, Heinecke's team suggests that HDL selectively modulates the expression of IFN-β, therefore affecting the type I INF response pathway, but not the type II INF pathway.
In an accompanying editorial, Alan Fogelman, from the University of California, Los Angeles, USA, said that the actions of HDL were independent of the interaction of HDL with ATP-binding cassette transporter ABCA1 or ABCG1, the cholesterol content of macrophages, or the inhibition of LPS binding to CD14 or TRL-4 on the cell surface.
"Localization of TRAM to the plasma membrane depends on its ability to bind to plasma membrane lipids, and thus it is likely that the actions of HDL reported by [the researchers] relate to some component of HDL that binds or modifies lipids in the cell membrane."
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By Nikki Withers