Role of Front and Back Signaling in Regulation of Neutrophil Polarization, Directionality, and In Vivo Infiltration.

摘要

Neutrophils play important roles in innate immunity and acute inflammatory responses. During an inflammatory response, neutrophils extravasate across the endothelium to arrive at the site of inflammation through a multistep process. However, the regulation of their recruitment has not been completely characterized. In my first project, we investigated the roles of PIP5K1C in neutrophil recruitment and showed that Pip5k1c-deficiency impaired neutrophil recruitment due to an adhesion defect rather than chemotactic defects. PIP5K1C regulates the adhesion through facilitating RhoA and integrin activation by chemoattractants. We also found that integrins could induce PIP5K1C-90 polarization in neutrophils through intracellular vesicle transport independently of any exogenous chemoattractant. This PIP5K1C-90 polarization is required for polarized RhoA activation at uropods and provides an initial directional cue for neutrophil polarization on the endothelium. Importantly, the polarization alleviates the inhibition of lamellipodium formation by RhoA so that neutrophils can form leading edges required for transendothelial migration. Because integrins are not known to regulate neutrophil polarization, our study has revealed a previously underappreciated role of integrin signaling in neutrophil regulation. In my second project, we characterized chemoattractant-activated signaling mechanisms that regulate actin cytoskeleton reorganization, which are critical for neutrophil polarization and chemotaxis. We demonstrated that Both PLCβ-PKC and PI3K-AKT pathways regulate F-actin polarization and chemotaxis through GSK phosphorylation. The relative contribution of this GSK3-mediated pathway to the regulation of neutrophil chemotaxis depended on neutrophil polarity preset by integrin-induced polarization of PIP5K1C. This study not only provides new insights into the regulation of actin cytoskeleton remodeling by chemoattractant, but also demonstrates the role of the interaction of different signaling pathways in regulating neutrophil polarization and chemotaxis.