TY - JOUR
T1 - Inhibition of integrin αdβ2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation
AU - Cui, Kui
AU - Podolnikova, Nataly P.
AU - Bailey, William
AU - Szmuc, Eric
AU - Podrez, Eugene A.
AU - Byzova, Tatiana V.
AU - Yakubenko, Valentin P.
N1 - Publisher Copyright:
© 2019 Cui et al.
PY - 2019/9/27
Y1 - 2019/9/27
N2 - 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 αDβ2 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 forαDβ2.CEPadduct withECM is generated during inflammation-mediated lipid peroxidation. The goal of this project was to identify a specific inhibitor for αDβ2-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 αD-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 αD-deficient mice. The tracking of adoptively transferred, fluorescently labeled WT and αD -/- monocytes in the model of peritoneal inflammation and in vitro two-dimensional and three-dimensional migration assays demonstrated thatP5peptide does not affectmonocytetransendothelial migration or macrophage efflux from the peritoneal cavity but regulates macrophage migration through the ECM. Moreover, the injection ofP5peptide intoWTmiceona high-fat diet prevents macrophage accumulation in adipose tissue in anαDβ2-dependent manner.Takentogether, these resultsdemonstratetheimportance of αDβ2-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.
AB - 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 αDβ2 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 forαDβ2.CEPadduct withECM is generated during inflammation-mediated lipid peroxidation. The goal of this project was to identify a specific inhibitor for αDβ2-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 αD-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 αD-deficient mice. The tracking of adoptively transferred, fluorescently labeled WT and αD -/- monocytes in the model of peritoneal inflammation and in vitro two-dimensional and three-dimensional migration assays demonstrated thatP5peptide does not affectmonocytetransendothelial migration or macrophage efflux from the peritoneal cavity but regulates macrophage migration through the ECM. Moreover, the injection ofP5peptide intoWTmiceona high-fat diet prevents macrophage accumulation in adipose tissue in anαDβ2-dependent manner.Takentogether, these resultsdemonstratetheimportance of αDβ2-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.
UR - http://www.scopus.com/inward/record.url?scp=85072712215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072712215&partnerID=8YFLogxK
U2 - 10.1074/jbc.RA119.009590
DO - 10.1074/jbc.RA119.009590
M3 - Article
C2 - 31395659
AN - SCOPUS:85072712215
SN - 0021-9258
VL - 294
SP - 14370
EP - 14382
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 39
ER -