Abstract 15129: Myeloperoxidase Attracts Neutrophils by Physical Forces
Background: Myeloperoxidase (MPO), a highly cationic heme enzyme abundantly expressed and released by polymorphonuclear neutrophils (PMN), has emerged as an important mediator in vascular inflammatory diseases. As MPO avidly binds to vascular matrix proteins, endothelial cells and the neutrophil membrane itself, we tested, whether the affinity of MPO to PMN and the vessel wall affects PMN recruitment.
Methods and Results: In-vitro chemotaxis assays revealed, that MPO initiated profound and highly directed PMN motility, which proved to be protein-specific, irrespective of MPO's catalytic activity and independent of intracellular signaling cascades of PMN. In fact, MPO-mediated motility appeared to reflect electrostatic interactions between the cationic MPO and the anionic neutrophil surface. In-vivo, MPO-deficient (Mpo−/−) mice displayed markedly reduced hepatic PMN infiltration compared to wild type (WT) mice in a model of hepatic ischemia and reperfusion (n=9, 287.5 vs 460.3 PMN/10 hpf, p<0.05). Moreover, intravital microscopy of cremaster muscle postcapillary venules revealed significantly impaired PMN adhesion and extravasation upon TNF-α treatment in Mpo−/− mice in comparison to WT mice (n=4, 492.8 vs 755.1 adherent PMN/mm2, p<0.05; 600 vs 1129 extravascular PMN/mm2, p<0.05). Hepatic and intrascrotal administration of active as well as mutant inactive MPO in WT mice provoked profound hepatic (n=8, 25.4 (ctrl) vs 45.6 (active MPO), 178.5 (inactive MPO), p<0.001) and cremasteric (n=4, 297.5 (ctrl) vs 1107.2 (active MPO), 1175.3 (inactive MPO) adherent PMN/mm2, p<0.001; 311.9 (ctrl) vs 1785.1 (active MPO), 2470.2 (inactive MPO) extravascular PMN/mm2, p<0.01) PMN accumulation, respectively.
Conclusions: Electrostatic interactions of MPO with the neutrophil surface initiate the attraction of PMN — not only representing a novel mechanism of neutrophil motility but also highlighting a so far unrecognized role for MPO in PMN recruitment. This alternative function of MPO, which is irrespective of the enzyme's catalytic activity, further sheds light on the diverse proinflammatory properties of this protein and calls for treatment strategies, which reach beyond the appreciation of MPO-derived oxidants.
- © 2010 by American Heart Association, Inc.