Oxidized phospholipids induce mononuclear cell specific inflammation involving CCR2

Abstract

Persistent mononuclear inflammation is a hallmark of chronic inflammatory diseases such as rheumatoid arthritis or atherosclerosis. However, the factors that determine monocyte specificity in chronically inflamed tissue are not known. Using the air pouch model, we show here that oxidized phospholipids (OxPL) that are formed in chronically inflamed tissue induce accumulation of monocytes, but not neutrophils, in the airpouch tissue. To understand the mechanism by which OxPL induce monocyte-specific inflammation, we analysed chemokine expression patterns in the air pouch tissue. OxPL induced expression of a specific set of chemokines, including MCP-1, 2 and 3, RANTES and GRO-α, however, to a lesser degree and with different kinetics than LPS. Furthermore, OxPL-induced monocyte accumulation was abrogated in CCR-2-deficient mice. In contrast to LPS, OxPL did not induce endothelial adhesion molecules E-selectin, VCAM-1 or ICAM-1. While LPS induced leukocyte accumulation in the air pouch tissue as well as in the lumen, OxPL mediated prolonged arrest of monocytes in the tissue. We show that the receptor for MCPs, CCR2, but not the RANTES receptor CCR5, was downregulated by OxPL, which could explain the arrest of the mononuclear cells. These data demonstrate that oxidative modification of OxPL in chronically inflamed tissue results in “low grade inflammation” mediating specific mononuclear cell accumulation via changes of the expression pattern of chemokines and their receptors, especially of the CCL2/CCR2 axis.