Lysophosphatidylcholine Triggers TLR2- and TLR4-Mediated Signaling Pathways but Counteracts LPS-Induced NO Synthesis in Peritoneal Macrophages by Inhibiting NF-κB Translocation and MAPK/ERK Phosphorylation

Abstract

BackgroundLysophosphatidylcholine (LPC) is the main phospholipid component of oxidized low-density lipoprotein (oxLDL) and is usually noted as a marker of several human diseases, such as atherosclerosis, cancer and diabetes. Some studies suggest that oxLDL modulates Toll-like receptor (TLR) signaling. However, effector molecules that are present in oxLDL particles and can trigger TLR signaling are not yet clear. LPC was previously described as an attenuator of sepsis and as an immune suppressor. In the present study, we have evaluated the role of LPC as a dual modulator of the TLR-mediated signaling pathway.Methodology/Principal FindingsHEK 293A cells were transfected with TLR expression constructs and stimulated with LPC molecules with different fatty acid chain lengths and saturation levels. All LPC molecules activated both TLR4 and TLR2-1 signaling, as evaluated by NF-қB activation and IL-8 production. These data were confirmed by Western blot analysis of NF-қB translocation in isolated nuclei of peritoneal murine macrophages. However, LPC counteracted the TLR4 signaling induced by LPS. In this case, NF-қB translocation, nitric oxide (NO) synthesis and the expression of inducible nitric oxide synthase (iNOS) were blocked. Moreover, LPC activated the MAP Kinases p38 and JNK, but not ERK, in murine macrophages. Interestingly, LPC blocked LPS-induced ERK activation in peritoneal macrophages but not in TLR-transfected cells.Conclusions/SignificanceThe above results indicate that LPC is a dual-activity ligand molecule. It is able to trigger a classical proinflammatory phenotype by activating TLR4- and TLR2-1-mediated signaling. However, in the presence of classical TLR ligands, LPC counteracts some of the TLR-mediated intracellular responses, ultimately inducing an anti-inflammatory phenotype; LPC may thus play a role in the regulation of cell immune responses and disease progression.

PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway

“…Nuclear and cytoplasmic protein was extracted to determine the translocation of NF-kB. Our data showed that LPS increased the translocation of NF-kB p50 and p65 from the cytoplasm into the nucleus, which is consistent with previous studies (Carneiro et al 2013). As we have expected, application of WY-14643 increased the accumulation of NF-kB p50 and p65 in the cytoplasm and the nuclear translocation of NF-kB caused by LPS was interrupted.…”

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

“…The precise nature of the endothelial LPC receptor is unknown, but this lipid has been reported to act as a multiactivity ligand, binding a number of proteins including: the CD36 scavenger receptor, Toll-like receptors (TLR4 and TLR2), and also the lectin-like oxLDL receptor-1 (LOX-1), after which it triggers a range of prooxidant and proinflammatory pathways (27)(28)(29). Studies also implicate G protein-coupled receptors in mediating LPC function (30).…”

The effect of oxidized phospholipids on phenotypic polarization and function of macrophages

“…Compared to conventional TLR2 agonists, such as lipoteichoic acid (LTA) or Pam 3 CSK 4 , OxPL have been shown to function as weak agonists for TLR2, with agonistic activity mainly residing in the long-chain fraction of OxPAPC[87]. Previously, only LysoPC[126] and LysoPS[127] purified species have been shown to activate TLR2. Based on these studies, the activation of TLR2 is not head group specific, as noted by the inclusion of both PC and PS head groups in the TLR2-activating lipids.…”