The role of innate immunity in atherogenesis

Karsten Hartvigsen, Meng-Yun Chou, Lotte F. Hansen, Peter X. Shaw, Sotirios Tsimikas, Christoph J. Binder, and Joseph L. Witztum

Medicine, University of California, San Diego, La Jolla, CA 92093

Corresponding Author: jwitztum{at}ucsd.edu

Lipid peroxidation is a common event even in health, and greatly accelerated in proinflammatory settings such as hypercholesterolemia. Consequently, oxidation-specific epitopes are generated, which are proinflammatory and immunogenic, leading to both adaptive and innate responses. Because innate immune mechanisms utilize conserved, germline pattern recognition receptors (PRRs) that are preformed and present at birth, it is not obvious why they should bind to such epitopes. In this review, we put forward the hypothesis that because oxidation-specific epitopes are ubiquitous in both health and disease, and because they in essence represent “danger signals,” they constitute a class of pathogen associated molecular patterns (PAMPs), leading to the natural selection of multiple innate PRRs that target such epitopes. We suggest that apoptotic cells, and the blebs and microparticles released from such cells, all of which are rich in oxidation-specific epitopes and proinflammatory, constitute an endogenous set of selecting antigens. In turn, natural antibodies, scavenger receptors and soluble innate proteins, such as pentraxins, all represent PRRs that target such epitopes. We discuss the evidence for this hypothesis and the consequences of such responses in health and disease, such as atherosclerosis.

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