Malondialdehyde Epitopes as Targets of Immunity and the Implications for Atherosclerosis

Abstract

Accumulating evidence suggests that oxidation-specific epitopes (OSEs) constitute a novel class of damage-associated molecular patterns (DAMPs) generated during high oxidative stress but also in the physiological process of apoptosis. To deal with the potentially harmful consequences of such epitopes, the immune system has developed several mechanisms to protect from OSEs and to orchestrate their clearance, including IgM natural antibodies and both cellular and membranebound receptors. Here, we focus on malondialdehyde (MDA) epitopes as prominent examples of OSEs that trigger both innate and adaptive immune responses. First, we review the mechanism of MDA generation, the different types of adducts on various biomolecules and provide relevant examples for physiological carriers of MDA such as apoptotic cells, microvesicles (MV) or oxidized low-density lipoproteins (LDL). Based on recent insights, we argue that MDA epitopes contribute to the maintenance of homeostatic functions by acting as markers of elevated oxidative stress and tissue damage. We discuss multiple lines of evidence that MDA epitopes are proinflammatory and thus important targets of innate and adaptive immune responses. Finally, we illustrate the relevance of MDA epitopes in human pathologies by describing their capacity to drive inflammatory processes in atherosclerosis and highlighting protective mechanisms of immunity that could be exploited for therapeutic purposes. Keywords inflammation; atherosclerosis; oxidative stress; immunity; malondialdehyde; oxidized low density lipoprotein; oxidation-specific epitopes; damage-associated molecular pattern OverviewCellular stress, senescence, and cell death are tightly associated with oxidative stress. A major consequence of increased oxidative stress is the peroxidation of membrane lipids resulting in the generation of various oxidation specific epitopes (OSEs). OSEs and the immune responses targeting them have been implicated in many acute and chronic inflammatory diseases, most prominently atherosclerosis. Studies of the biological activities of oxidized LDL (OxLDL), which is a key pathogenic driver of atherosclerosis, have helped identify OSE as a novel class of damage-associated molecular patterns (DAMPs). In this

Malondialdehyde epitopes as mediators of sterile inflammation

“…Modification of proteins by chemical derivatization in vitro has allowed studying MDA-mediated effects on a variety of carriers ranging from myelin proteins [53] to wheat peptides [54]. Reported observations of proteins modified in vivo with MDA were recently summarized by us elsewhere [16]. Here, we select several exemplary proteins shown to carry MDA epitopes in vivo for discussion with respect to their role in inflammatory diseases.…”

“…Many more proteins have been identified as in vivo carriers of MDA epitopes (see [16] for an extensive list), including elongation factor-2 [68], cartilage collagen [69], and Surfactant…”

“…Both humoral and cellular mechanisms for recognition of MDA epitopes have been identified but here we will focus on cellular responses as humoral components with specificity for MDA epitopes have been discussed by us elsewhere in detail [16]. Cellular responses have been…”

“…are capable of forming covalent adductions with target molecules such as proteins, with important physiological consequences[16]. MDA has been reported to be the most abundant aldehyde generated during lipid peroxidation as demonstrated by Esterbauer et al in several in vitro oxidation studies, where the authors found that 4-HNE generation only amounts to 10% of that of MDA…”

Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice

“…Increased oxidative stress is associated with tissue injury and inflammation where an accumulation of free radicals results in the generation of lipid decomposition products such as malondialdehyde (MDA) . MDA can covalently modify self‐molecules such as proteins or phospholipids and form hapten‐like moieties termed “MDA epitopes.” These and other oxidative modifications are collectively called “oxidation‐specific epitopes” (OSEs) and have been found on the surface of dying cells in vitro as well as in many inflammatory pathologies including atherosclerosis .…”