Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

Abstract

Aims: Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE. Results: IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFjB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice. Innovation: These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects. Conclusion: PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions. Antioxid. Redox Signal. 22, 1633-1645.

Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro

“…While 4-HNE typically induces JNK and p38 MAPK activation in HSCs [7,8] and in other cell types [39,52] it does not have significant effects on either Ras/ERK [7] or NF-kB [8]. Considering the lack of IsoLG-mediated NF-kB activation in hHSC while there is evidence that 15-E 2 -IsoLG strongly activates NF-kB in macrophages, this confirms previous observations suggesting a strong celltype dependency in the response to this mediator [30]. Similarly, we did not detect any significant activation of p38 MAPK, a known target of ER stress activation [20,47].…”

“…Overall, the most profound effect of hHSC exposure to IsoLG is an effect on the synthesis and secretion of pro-inflammatory cytokines/chemokines. Such direct pro-inflammatory and activating effects have also been demonstrated in immune cells such as macrophages [30], and dendritic cells [27]. Whilst HSC are not traditionally considered as the main hepatic immune cell type, they contribute to tissue inflammation by providing chemotactic signals that regulate their interaction with inflammatory cell types, as well as HSC themselves [53,54].…”

“…With respect to their potential role in liver disease, IsoLGs adducts have been described in livers of rodents exposed acutely to carbon tetrachloride [16], and chronically to ethanol [28,29], or high fat diet [30]. However, IsoLGs's effects on specific hepatic cell types and their potential contribution to disease pathogenesis have not been investigated.…”

“…In other cell types, IsoLGs exposure promotes a proinflammatory phenotype, via upregulation of adhesion molecules, chemokines/cytokines, and transcription factors [20,27,30]. Therefore, we investigated if incubation of HSCs with IsoLGs had similar effects by measuring mRNA levels of multiple pro-inflammatory mediators [37].…”

Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

“…Isolevuglandin-PE contributes to an NFkB-dependent inflammatory response in macrophages exposed to isolevuglandins by a mechanism involving binding to the receptor for advanced glycation end-products (RAGE). Moreover, isoLG adducts of PE were increased in hyperlipidemic and inflammatory conditions, such familial hypercholesterolemia in humans and high-fat diet induced obesity and hepatosteatosis in mice [75]. Analogous compounds called neuroketals can be formed from DHA via H 4 -neuroprostanes; these have been detected in brain tissue and age-related increases in protein adducts observed [76].…”