Influence of non-enzymatically glycated collagen on monocyte–macrophage differentiation

Blood monocytes (mo) on transendothelial migration interact with extracellular matrix components (ECM) and differentiate into macrophages (mφ), which play an important role in both physiological, and pathological conditions, particularly, atherosclerosis. In order to study whether modification of ECM such as non-enzymatic glycation occurring in diabetes influences mo–mφ differentiation, an in vitro system using isolated human peripheral blood mononuclear cells (PBMC) maintained on non-enzymatically glycated COL I (NEG COL I) was used. Mφ specific functions such as receptor mediated endocytosis of modified proteins, production of mφ specific 92 and 72 kDa matrix metalloproteinases (MMPs), expression of surface antigen and loss of myeloperoxidase (MPO) activity were assessed. Endocytosis of 125[I] acetyl BSA was significantly higher in cells maintained on NEG COL I than those on COL I. Kinetic analysis revealed that the rate of uptake of modified BSA and production of MMPs by cells maintained on NEG COL I were higher than those on COL I suggesting a faster rate of differentiation of cells maintained on modified substrata. FACS analysis of the expression of surface antigen showed that the rate of down-regulation of monocyte specific CD14 and the rate of up-regulation of mφ specific CD71 were high in cells maintained on NEG COL I. These results suggest that the interaction of monocyte with non-enzymatically glycated matrix protein in the vessel wall may result in faster rate of induction of mo–mφ differentiation leading to foam cell formation, a critical early event in the initiation and development of atherosclerosis.