Binding to the Fc portion of antibodies attached directly to pathogens or to the surface of infected cells allows enhanced uptake and clearance by cells equipped with an FcR

Binding to the Fc portion of antibodies attached directly to pathogens or to the surface of infected cells allows enhanced uptake and clearance by cells equipped with an FcR. lines of evidence that MDA epitopes are pro-inflammatory 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. strong class=”kwd-title” Keywords: inflammation, atherosclerosis, oxidative stress, immunity, malondialdehyde, oxidized low density lipoprotein, oxidation-specific epitopes, damage-associated molecular pattern 1.?Overview Cellular 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 chapter we will particularly focus on a certain group of OSEs, namely malondialdehyde (MDA) epitopes. MDA epitopes have been documented on the surface of dying cells and in damaged tissues. Recent studies have identified them as major targets of various immune responses that modulate homeostatic processes, e.g. the clearance of apoptotic cells. In atherosclerosis, which is usually characterized by impaired resolution and chronic inflammation, MDA epitopes have been identified as mediators of inflammation and therefore serve as interesting potential targets for immunological therapeutic interventions in CVDs. HDAC8-IN-1 2.?Biochemistry and generation of MDA in vitro and in vivo Oxygen is a fundamental prerequisite for energy production by cellular respiration in aerobic organism. However, this also results in the constant generation of reactive oxygen species (ROS) as potentially damaging by-products, which are produced endogenously in mitochondria, HDAC8-IN-1 peroxisomes, the endoplasmic reticulum and even in the plasma membrane of cells, but can also be induced Rabbit Polyclonal to PTRF exogenously by UV light, heat, bacterial and environmental agents, such as tobacco smoke and ionizing radiation (Bae, Oh, Rhee, & Yoo, 2011; Nathan & Cunningham-Bussel, 2013). Newly generated ROS can attack membrane lipids made up of carbon-carbon double bonds (e. g. poly-unsaturated fatty acids (PUFAs) of phospholipids), and damage them by HDAC8-IN-1 a process called lipid peroxidation. Lipid peroxidation of free fatty acids occurs through both enzymatic and non-enzymatic mechanisms. If not efficiently controlled this emanates in the perturbed integrity of different cellular structures potentially leading to cellular death (Nathan & Cunningham-Bussel, 2013). Enzymatic mechanisms involve the activation of lipoxygenases, myeloperoxidases, cyclooxygenases, and cytochrome P450 (Niki, 2009). After the enzymatic removal of hydrogen from the double allylic-activated CH2 group of PUFAs, oxygen is added, generating a peroxydienyl radical. This is then transformed into an anion and the reaction is usually terminated by back-transfer of the proton generated in the first reaction step, resulting in the formation of a lipid-hydroperoxide molecule (LOOH). Non-enzymatic mechanisms are mediated by free radicals, which can be indirectly generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and nitric-oxide synthases (Niki, 2009). In turn, free radicals are able to remove hydrogen from a CH2 group of PUFAs, resulting in the generation of lipid-hydroperoxide molecules (LOOH) and new dienyl radicals, which propagate this chain reaction. LOOHs that are generated by both reactions then decompose and during their degradation a great HDAC8-IN-1 variety of secondary products such as MDA, 4-hydroxynonenal (4-HNE) and the remaining core aldehyde of.