Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

Abstract

Oxidized low-density lipoprotein (OxLDL), which contains hundreds of different oxidized lipid molecules, is a hallmark of hyperlipidemia and atherosclerosis. The same oxidized lipids found in OxLDL are also formed in apoptotic cells, and are present in tissues as well as in the circulation under pathological conditions. In many disease contexts, oxidized lipids constitute damage signals, or patterns, that activate pattern-recognition receptors (PRRs) and significantly contribute to inflammation. Here, we review recent discoveries and emerging trends in the field of oxidized lipids and the regulation of inflammation, focusing on oxidation products of polyunsaturated fatty acids esterified into cholesteryl esters (CEs) and phospholipids (PLs). We also highlight context-dependent activation and biased agonism of Toll-like receptor-4 (TLR4) and the NLRP3 inflammasome, among other signaling pathways activated by oxidized lipids.

Keywords: inflammasome; inflammation; oxidized lipid; toll-like receptor.

Figure 1. Context-dependent adverse and protective effects of oxidized lipids

This chart summarizes, in an abbreviated format, major adverse and protective effects of key oxidized lipids reviewed in this article. It also emphasizes that a specific cellular response to oxidized lipids can have adverse and/or protective effects, depending on the tissue and pathology context. OxPC, oxidized phosphatidylcholine; OxPE, oxidized phosphatidylethanolamine; OxCE, oxidized cholesteryl ester; MDA, malondialdehyde [including MDA derivatives, such as MAA (malondialdehyde-acetaldehyde)]; CEP, 2-(ω-carboxyethyl)pyrrole [oxidation end product of DHA (docosahexaenoic acid)].

Figure 2. NLRP3 inflammasome induction in ECs

Acting as DAMPs, OxLDL, OxPL, and disturbed flow, increase oxidative stress in the endothelium leading to the induction of SREBP2 promoting the downstream transcriptional activation of NLRP3, NOX2, and miR-92a. Consequently, the inflammasome component proteins (e.g., NLRP3) and oxidative burden in ECs are increased, which result in the induction of the NLRP3 inflammasome. As a result of elevated levels of IL-1β, the innate immune response in ECs is augmented, exemplified by the increased expression of MCP-1, VCAM-1, ICAM-1, and E-selectin. The SREBP2-induced miR-92a targets SIRT1, KLF2, and KLF4, which leads to the dysfunctional endothelium. Collectively, oxidized lipids, acting via the NLRP3 inflammasome, contribute to an atherogenic phenotype of ECs.