Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products

Abstract

Rationale Oxidative stress is an important contributing factor in a number of human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid DHA, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have pro-angiogenic and pro-inflammatory functions. While CEP is continuously accumulated during chronic processes such as tumor progression and atherosclerosis, its levels during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism. Objective To identify the cellular and molecular mechanism for CEP clearance. Methods and Results Here we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80hi and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared to F4/80lo and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on two receptors expressed by macrophages, CD36 and TLR2. While knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages’ ability to scavenge CEP derivatives of proteins. Conclusions Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.

TLR2 Plays a Key Role in Platelet Hyperreactivity and Accelerated Thrombosis Associated With Hyperlipidemia

“…23, 24, 46, 47 Such interactions potentiate the function of pattern recognition receptors and augment the inflammatory response to microbial ligands. 46, 48 It has been suggested that epitopes generated by peroxidation of lipids and lipoproteins resemble microbial wall epitopes, and recognition of such epitopes by scavenger receptors plays a role in homeostasis and immunity.…”

Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

“…In turn, HOHA reacts with protein ε-amino groups or with a primary amino group of PE and produces 2-(ω-carboxyethyl)pyrrole (CEP) [79, 80]. CEP-modified proteins have been detected in the retina of patients with AMD [79], during wound healing and in vascularized tumors [81], in atherosclerotic lesions and in hyperlipidemic plasma [82]. TLR2 has been identified as a receptor on endothelial cells that recognizes the CEP modification and mediates cellular activation [81].…”

CEP Is an Important and Ubiquitous Oxidation Specific Epitope Recognized by Innate Pattern Recognition Receptors

“…This suggests that a motif common to both a pathogen (PAMP) and OSE (DAMP)-such as PC-will have exerted selective pressure for the conservation of a set of innate PRRs to maintain homeostasis against the common DAMP/PAMP. 14 In turn, this leads to the prediction that in a similar manner, there will be a set of innate PRRs that will have been selected to recognize other important pathological motifs, such as CEP, an OSE that is the subject of the manuscript by Kim et al 16 in the current issue of Circulation Research.…”

“…In the current studies, they extend these studies to demonstrate that CEP levels accumulate progressively in melanomas in mice over time as the tumor progresses, and that plasma and arterial levels of CEP are substantially elevated in western diet (WD) - fed Apoe −/− mice. 16 …”

“…In the current manuscript by Kim et al, 16 the authors present important new studies that now begin to address the mechanisms by which CEP are cleared from tissues. Utilizing a variety of elegant in vitro and in vivo techniques, they convincingly demonstrate that macrophages use the PRRs CD36 and TLR2, individually or cooperatively, to bind to and mediate tissue removal of CEP decorated proteins.…”