Inhibition of integrin α D β 2 -mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation

• Published in: The Journal of biological chemistry Vol. 294; no. 39; p. 14370
• Main Authors: Cui, Kui, Podolnikova, Nataly P, Bailey, William, Szmuc, Eric, Podrez, Eugene A, Byzova, Tatiana V, Yakubenko, Valentin P
• Format: Journal Article
• Language: English
• Published: United States 27.09.2019
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Cell Movement; Cells, Cultured; HEK293 Cells; Humans; Integrin alpha Chains - metabolism; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - physiology; Mice; Mice, Inbred C57BL; Peptides, Cyclic - pharmacology; Peptides, Cyclic - therapeutic use; Peritonitis - drug therapy; Peritonitis - etiology; Protein Binding; Pyrroles - metabolism; Thioglycolates - toxicity; inflammation; migration; macrophage; adhesion; integrin; integrin αDβ2
• ISSN: 1083-351X

A critical step in the development of chronic inflammatory diseases is the accumulation of proinflammatory macrophages in the extracellular matrix (ECM) of peripheral tissues. The adhesion receptor integrin α β promotes the development of atherosclerosis and diabetes by supporting macrophage retention in inflamed tissue. We recently found that the end product of docosahexaenoic acid (DHA) oxidation, 2-(ω-carboxyethyl)pyrrole (CEP), serves as a ligand for α β CEP adduct with ECM is generated during inflammation-mediated lipid peroxidation. The goal of this project was to identify a specific inhibitor for α β -CEP interaction that can prevent macrophage accumulation. Using a specially designed peptide library, Biacore-detected protein-protein interaction, and adhesion of integrin-transfected HEK 293 cells, we identified a sequence (called P5 peptide) that significantly and specifically inhibited α -CEP binding. In the model of thioglycollate-induced peritoneal inflammation, the injection of cyclic P5 peptide reduced 3-fold the macrophage accumulation in WT mice but had no effect in α -deficient mice. The tracking of adoptively transferred, fluorescently labeled WT and α monocytes in the model of peritoneal inflammation and two-dimensional and three-dimensional migration assays demonstrated that P5 peptide does not affect monocyte transendothelial migration or macrophage efflux from the peritoneal cavity but regulates macrophage migration through the ECM. Moreover, the injection of P5 peptide into WT mice on a high-fat diet prevents macrophage accumulation in adipose tissue in an α β -dependent manner. Taken together, these results demonstrate the importance of α β -mediated macrophage adhesion for the accumulation of infiltrating macrophages in the inflamed ECM and propose P5 peptide as a potential inhibitor of atherogenesis and diabetes.