Oxidative Modifications of Extracellular Matrix Promote the Second Wave of Inflammation via B₂ Integrins

Creator(s)

Valentin P. Yakubenko, Cleveland Clinic FoundationFollow
Kui Cui, Quillen-Dishner College of Medicine
Christopher L. Ardell, Quillen-Dishner College of Medicine
Kathleen E. Brown, Cleveland Clinic Foundation
Xiaoxia Z. West, Cleveland Clinic Foundation
Detao Gao, Cleveland Clinic Foundation
Samantha Stefl, Cleveland Clinic Foundation
Robert G. Salomon, Case Western Reserve University
Eugene A. Podrez, Cleveland Clinic Foundation
Tatiana V. Byzova, Cleveland Clinic Foundation

Document Type

Article

Publication Date

7-5-2018

Description

Early stages of inflammation are characterized by extensive oxidative insult by recruited and activated neutrophils. Secretion of peroxidases, including the main enzyme, myeloperoxidase, leads to the generation of reactive oxygen species. We show that this oxidative insult leads to polyunsaturated fatty acid (eg, docosahexaenoate), oxidation, and accumulation of its product 2-(v-carboxyethyl)pyrrole (CEP), which, in turn, is capable of protein modifications. In vivo CEP is generated predominantly at the inflammatory sites in macrophage-rich areas. During thioglycollate-induced inflammation, neutralization of CEP adducts dramatically reduced macrophage accumulation in the inflamed peritoneal cavity while exhibiting no effect on the early recruitment of neutrophils, suggesting a role in the second wave of inflammation. CEP modifications were abundantly deposited along the path of neutrophils migrating through the 3-dimensional fibrin matrix in vitro. Neutrophil-mediated CEP formation was markedly inhibited by the myeloperoxidase inhibitor, 4-ABH, and significantly reduced in myeloperoxidase-deficient mice. On macrophages, CEP adducts were recognized by cell adhesion receptors, integrin aMb2 and aDb2. Macrophage migration through CEP-fibrin gel was dramatically augmented when compared with fibrin alone, and was reduced by b2-integrin deficiency. Thus, neutrophil-mediated oxidation of abundant polyunsaturated fatty acids leads to the transformation of existing proteins into stronger adhesive ligands for aMb2- and aDb2-dependent macrophage migration. The presence of a carboxyl group rather than a pyrrole moiety on these adducts, resembling characteristics of bacterial and/or immobilized ligands, is critical for recognition by macrophages. Therefore, specific oxidation-dependent modification of extracellular matrix, aided by neutrophils, promotes subsequent aMb2- and aDb2-mediated migration/retention of macrophages during inflammation.

Citation Information

Yakubenko, Valentin P.; Cui, Kui; Ardell, Christopher L.; Brown, Kathleen E.; West, Xiaoxia Z.; Gao, Detao; Stefl, Samantha; Salomon, Robert G.; Podrez, Eugene A.; and Byzova, Tatiana V.. 2018. Oxidative Modifications of Extracellular Matrix Promote the Second Wave of Inflammation via B₂ Integrins. Blood. Vol.132(1). 78-88. https://doi.org/10.1182/blood-2017-10-810176 PMID: 29724896 ISSN: 0006-4971