Receptor-Mediated Mechanism Controlling Tissue Levels of Bioactive Lipid Oxidation Products
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.
- Lipid oxidation
- Toll-like receptor 2
- oxidized lipids
- wound healing
- Received December 23, 2014.
- Revision received May 8, 2015.
- Accepted May 12, 2015.