Inhibition of integrin αdβ2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation

Kui Cui, Nataly P. Podolnikova, William Bailey, Eric Szmuc, Eugene A. Podrez, Tatiana V. Byzova, Valentin P. Yakubenko

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)14370-14382
Number of pages13
JournalJournal of Biological Chemistry
Volume294
Issue number39
DOIs
StatePublished - Jan 1 2019

Fingerprint

Docosahexaenoic Acids
Macrophages
Integrins
Adhesion
Inflammation
Oxidation
Pyrroles
Extracellular Matrix
Tissue
Medical problems
Atherosclerosis
Thioglycolates
Peptide Library
Cyclic Peptides
Peptides
Injections
HEK293 Cells
Peritoneal Cavity
High Fat Diet
Nutrition

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Inhibition of integrin αdβ2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation. / Cui, Kui; Podolnikova, Nataly P.; Bailey, William; Szmuc, Eric; Podrez, Eugene A.; Byzova, Tatiana V.; Yakubenko, Valentin P.

In: Journal of Biological Chemistry, Vol. 294, No. 39, 01.01.2019, p. 14370-14382.

Research output: Contribution to journalArticle

Cui, Kui ; Podolnikova, Nataly P. ; Bailey, William ; Szmuc, Eric ; Podrez, Eugene A. ; Byzova, Tatiana V. ; Yakubenko, Valentin P. / Inhibition of integrin αdβ2-mediated macrophage adhesion to end product of docosahexaenoic acid (DHA) oxidation prevents macrophage accumulation during inflammation. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 39. pp. 14370-14382.
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