| First Author | Cui K | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 39 | Pages | 14370-14382 |
| PubMed ID | 31395659 | Mgi Jnum | J:282846 |
| Mgi Id | MGI:6383242 | Doi | 10.1074/jbc.RA119.009590 |
| Citation | Cui K, et al. (2019) Inhibition of integrin alphaDbeta2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation. J Biol Chem 294(39):14370-14382 |
| abstractText | 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 alphaDbeta2 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-(omega-carboxyethyl)pyrrole (CEP), serves as a ligand for alphaDbeta2 CEP adduct with ECM is generated during inflammation-mediated lipid peroxidation. The goal of this project was to identify a specific inhibitor for alphaDbeta2-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 alphaD-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 alphaD-deficient mice. The tracking of adoptively transferred, fluorescently labeled WT and alphaD (-/-) monocytes in the model of peritoneal inflammation and in vitro 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 alphaDbeta2-dependent manner. Taken together, these results demonstrate the importance of alphaDbeta2-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. |
