Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity

TY - JOUR

T1 - Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity

AU - Miller, Yury I

AU - Choi, Soo-Ho

AU - Wiesner, Philipp

AU - Fang, Longhou

AU - Harkewicz, Richard

AU - Hartvigsen, Karsten

AU - Boullier, Agnès

AU - Gonen, Ayelet

AU - Diehl, Cody J

AU - Que, Xuchu

AU - Montano, Erica

AU - Shaw, Peter X

AU - Tsimikas, Sotirios

AU - Binder, Christoph J

AU - Witztum, Joseph L

PY - 2011/1/21

Y1 - 2011/1/21

N2 - 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 "pathogen-associated 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 oxidation-specific 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.

AB - 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 "pathogen-associated 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 oxidation-specific 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.

KW - Animals

KW - Atherosclerosis

KW - Epitopes

KW - Humans

KW - Immunity, Innate

KW - Oxidation-Reduction

KW - Oxidative Phosphorylation

KW - Receptors, Pattern Recognition

U2 - 10.1161/CIRCRESAHA.110.223875

DO - 10.1161/CIRCRESAHA.110.223875

M3 - Journal article

C2 - 21252151

SN - 0009-7330

VL - 108

SP - 235

EP - 248

JO - Circulation Research

JF - Circulation Research

IS - 2

ER -