Oxidative modifications of extracellular matrix promote the second wave of inflammation via ß2 integrins.
Blood
; 132(1): 78-88, 2018 07 05.
Article
em En
| MEDLINE
| ID: mdl-29724896
ABSTRACT
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-(ω-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 αMß2 and αDß2 Macrophage migration through CEP-fibrin gel was dramatically augmented when compared with fibrin alone, and was reduced by ß2-integrin deficiency. Thus, neutrophil-mediated oxidation of abundant polyunsaturated fatty acids leads to the transformation of existing proteins into stronger adhesive ligands for αMß2- and αDß2-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 αMß2- and αDß2-mediated migration/retention of macrophages during inflammation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Movimento Celular
/
Antígeno de Macrófago 1
/
Antígenos CD18
/
Antígenos CD11
/
Cadeias alfa de Integrinas
/
Matriz Extracelular
/
Macrófagos
/
Neutrófilos
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article