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

Yury I. Miller, Soo Ho Choi, Philipp Wiesner, Longhou Fang, Richard Harkewicz, Karsten Hartvigsen, Agnès Boullier, Ayelet Gonen, Cody J. Diehl, Xuchu Que, Erica Montano, Peter X. Shaw, Sotirios Tsimikas, Christoph J. Binder, Joseph L. Witztum

Research output: Contribution to journalArticle

388 Scopus citations

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 "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.

Original languageEnglish (US)
Pages (from-to)235-248
Number of pages14
JournalCirculation Research
Volume108
Issue number2
DOIs
StatePublished - Jan 21 2011

Keywords

  • innate immunity
  • oxidation-specific epitopes
  • oxidized lipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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