Scavenger receptors are associated with cellular interactions of S100A12 in vitro and in vivo

Increased plasma levels of S100 proteins and interaction of S100 proteins with receptor for advanced glycation end products (RAGE) have been associated with a number of disease states, including chronic inflammatory processes and atherosclerosis. However, data concerning the role of circulating S100 proteins in these pathologies in vivo are scarce and, furthermore, it is currently not known whether RAGE is the sole receptor for extracellular S100 proteins in vivo. We report a novel methodology using recombinant human S100 proteins radiolabelled with fluorine-18, particularly, ¹⁸F-S100A12, in receptor binding studies and cellular association studies in vitro, and in dynamic small animal positron emission tomography (PET) studies in rats in vivo. Association to both human aortic endothelial cells and macrophages revealed specific binding of ¹⁸F-S100A12 to RAGE, but, furthermore, provides evidence for interaction of ¹⁸F-S100A12 to various scavenger receptors (SR). PET data showed temporary association of ¹⁸F-S100A12 with tissues overexpressing RAGE (e.g., lung), and, moreover, accumulation of ¹⁸F-S100A12 in tissues enriched in cells overexpressing SR (e.g., liver and spleen). Blockade of overall SR interaction by maleylated BSA (malBSA) clearly shows diminished in vivo association of ¹⁸F-S100A12 to these tissues as well as a significant increment of the mean plasma residence time of ¹⁸F-S100A12 (4.8 ± 0.4 h vs. 2.3 ± 0.3 h). The present approach first demonstrates that besides RAGE also scavenger receptors contribute to distribution, tissue association and elimination of circulating proinflammatory S100A12.