Journal
BLOOD
Volume 132, Issue 1, Pages 78-88Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-10-810176
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [DK102020]
- National Institutes of Health, National Heart, Lung, and Blood Institute [HL077213, HL126738, HL071625]
- National Institutes of Health, National Eye Institute [EY016813]
- National Institutes of Health [C06RR0306551]
- Canova endowment fund
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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-(omega-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 alpha(M)beta(2) and alpha(D)beta(2). Macrophage migration through CEP-fibrin gel was dramatically augmented when compared with fibrin alone, and was reduced by beta(2)-integrin deficiency. Thus, neutrophil-mediated oxidation of abundant polyunsaturated fatty acids leads to the transformation of existing proteins into stronger adhesive ligands for alpha(M)beta(2)- and alpha(D)beta(2)-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 alpha(M)beta(2)- and alpha(D)beta(2)-mediated migration/retention of macrophages during inflammation.
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