Oxidation-Specific Epitopes Are Danger-Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate Immunity

Abstract

-Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating "oxidation-specific" epitopes. In this review, we discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of "pattern recognition receptors" (PRRs). By analogy with microbial "pathogenassociated molecular patterns" (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent "danger (or damage)-associated molecular patterns" (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Furthermore, because many PAMPs on microbes share molecular identity and/or mimicry with oxidationspecific epitopes, such PAMPs provide a strong secondary selecting pressure for the same set of oxidation-specific PRRs as well. Because lipid peroxidation is ubiquitous and a major component of the inflammatory state associated with atherosclerosis, the understanding that oxidation-specific epitopes are DAMPs, and thus the target of multiple arcs of innate immunity, provides novel insights into the pathogenesis of atherosclerosis. As examples, we show that both cellular and soluble PRRs, such as CD36, toll-like receptor-4, natural antibodies, and C-reactive protein recognize common oxidation-specific DAMPs, such as oxidized phospholipids and oxidized cholesteryl esters, and mediate a variety of immune responses, from expression of proinflammatory genes to excessive intracellular lipoprotein accumulation to atheroprotective humoral immunity. These insights may lead to improved understanding of inflammation and atherogenesis and suggest new approaches to diagnosis and therapy. (Circ Res. 2011;108:235-248.) Key Words: oxidation-specific epitopes Ⅲ innate immunity Ⅲ oxidized lipids T he process of oxidative phosphorylation adopted by early ancestors of mitochondria has determined the evolution of eukaryotes as organisms deriving energy from oxidation of a substrate. Our lives are clearly oxygen-centric, and both oxidative phosphorylation and nonrespiratory oxygenation are vital parts of metabolism and signal transduction. How-

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…18 In addition, oxidation and other modifications of LDL can generate new epitopes that could be recognized as 'non-self' and therefore induce production of self-antibodies. 19 However, these oxidation-specific IgM antibodies are the innate immunity components, as they are produced constitutively and do not require T-cell-mediated induction. 20 These germline natural IgM antibodies are atheroprotective, as they are involved in the clearance of proatherogenic oxLDL.…”

“…If infection is absent, PRRs could be stimulated by damage-associated molecular patterns generated by dying and stressed cells, which in turn induces 'sterile inflammation'. 19,22 Indeed, 'sterile inflammation' and molecular mimicry with pathogens may represent the pathways by which self-antibodies specific to atherosclerosis-related antigens can contribute to atherogenesis. 1 In contrast to proatherogenic LDL, high-density lipoprotein (HDL) is atheroprotective.…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…Cellular damage or death results in the generation of damage/danger-associated molecular patterns (DAMPs) (17,78,108). DAMPs bind to pattern recognition receptors (PRR) on MP, resulting in the release of chemical mediators, such as cytokines and chemokines (96,106,107).…”

“…At the site of injury, the resident and infiltrating MP remove dead or dying cells and cellular debris. The composition of the material ingested by MP is essential in determining the downstream inflammatory response (22,108). For example, infection activates MP when microbial peptides or polysaccharide (also called pathogen-associated molecular patterns [PAMPs]) are recognized by PRR on their surface.…”

Five different phenotypes of endothelial cell cultures from the bovine corpus luteum: Present outcome and role of potential dendritic cells in luteolysis

“…Their activation triggers the powerful inflammatory cascade, which, in macrovessels, obviously contributes to atherosclerotic progress (Zhang YI and Zhang C, 2010;Miller et al, 2011). The CK + cell cultures, which were derived from the bovine aorta and vena cava and produce CK8, 18, and 19 as polypeptides (Spanel-Borowski et al 1994b), could be comparable with the microvascular type 1 from the CL.…”