Figure 1. The generation of OSEs.
Tissue damage, cellular stress and cell death result in increased oxidative stress, which promotes lipid peroxidation. Lipid peroxidation can occur through non-enzymatic mechanisms, such as reactive oxygen species (ROS), and through enzymatic mechanisms, including myeloperoxidases, 12/15-lipoxygenases, cyclooxygenases and cytochrome P450. The oxidation of sn-2 polyunsaturated fatty acids (PUFAs) of membrane phospholipids leads to fragmentation and the generation of highly reactive breakdown products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)8,30,31,32. In addition, different types of oxidized phospholipids (OxPLs) can be generated from different phospholipid backbones, including oxidized phosphatidylcholine, oxidized phosphatidylethanolamine (OxPE), oxidized phosphatidylserine (OxPS) and oxidized cardiolipin (OxCL). The newly generated breakdown products and the oxidized and truncated residual core OxPLs can in turn react with free amino groups of protein side chains or lipids that are localized in their vicinity, forming stable covalent adducts and creating oxidation-specific epitopes (OSEs). Because phosphocholine (PC) as an OSE is only presented as an epitope in the context of OxPL, these epitopes are termed PC-OxPLs for clarity. The PC moiety can also be a component of the capsular polysaccharide of bacteria, where it is not part of a phospholipid and is constitutively presented as an epitope. In addition, an adduct between an oxidative fragment of docosahexaenoic acid, (E)-4-hydroxy-7-oxohept-5-enoic acid and lysines of proteins (or aminophospholipids) can lead to the formation of 2-(ω-carboxyethyl) pyrrole (CEP). OSE-modified proteins or lipids are sensed by innate immune responses and represent a unique class of damage-associated molecular patterns (DAMPs).