Figure 8.

Model for C5a-mediated alterations on MV shedding for neutrophils after PT. PT causes an early activation of complement generating increased C5a concentrations. C5a induces activity of the small GTPase Arf6, which is dependent on C5aR1 signaling. Additionally, specific changes in gene expression pattern are involved in MV shedding. Resting PMNs show physiological MV shedding and composition, which have no inflammatory potential. In contrast, PMNs incubated with C5a loose C5aR1 surface expression induced by C5aR1 signaling and Arf6-mediated shedding of C5aR1-positive MVs. Furthermore, these MVs show increased CD66b and C5aR1 expression, which show pro-inflammatory features when incubated with resting PMNs. C5a induces shedding of MVs, which lead to NAPDH oxidase activation, ROS generation and MPO release in resting PMNs. Moreover, IL-6 generation was observed when these MVs were incubated in whole blood. PMX53 and the Arf6-selective compound NAV2729 can block the shedding of C5aR1-positive MVs from PMN surfaces and its inflammatory effects.