The down regulation of neutrophil oxidative metabolism by S100A8 and S100A9: Implication of the protease-activated receptor-2

S100A8 and S100A9 regulate polymorphonuclear neutrophils (PMNs) recruitment and represent 40% of PMN cytosolic protein weight. We have shown that S100A8/S100A9 inhibit PMN oxidative metabolism. The present study was designed to elucidate the mechanisms of this anti-oxidative effect. We hypothesized that the protease activated receptor-2 (PAR-2) played a role in the down-regulation of PMN oxidative metabolism by S100A8/S100A9.Freshly isolated PMNs were tested for their ability to oxidize dichlorofluorescin-diacetate. Functional inhibition of PAR-2 with ENMD-1068, the pepducin P2pal-21 or an antibody directed at PAR-2 cleavage/activation site, resulted in a significant inhibition of S100A8 and S100A9 anti-oxidative effect. Conversely, the controlled activation of PAR-2 potentiated S100 anti-oxidative effect.Taken together, the data indicate that the anti-oxidative effect of S100A8/A9 is initiated by PAR-2 activation. S100A8/S100A9 may therefore dampen inflammation without interfering with its initial strength. This finding opens translational possibilities to limit deleterious PMN activation with a dual PAR-2/S100 strategy.

► The inhibition of PAR-2 reduces the induction of the oxidative metabolism of PMNs by LPS.
► The inhibition of PAR-2 also reduces the anti-oxidative effect of calprotectin.
► The controlled activation of PAR-2 amplifies the anti-oxidative effect of calprotectin.
► The role of PAR-2 in calprotectin anti-oxidative effect can not be explained by a direct effect of calprotectin on PAR-2.