Regulators and Effectors of Arf GTPases in Neutrophils

Figure 1

Main steps in PMN transmigration and regulation of PMN functional responses by Arfs and their regulators. (a) Schematic representation of PMN extravasation in infectious and noninfectious diseases. The first contact with endothelial cells is mediated by engagement of selectins with their counterreceptor P-selectin glycoprotein ligand-1 (PSGL-1) which results in capture and rolling of PMNs. Activation of PMNs by selectins and the different inflammatory signals like chemokines while rolling induces activation of the β₂ integrins (LFA-1 and Mac-1) and slow rolling. Binding of activated β₂ integrins to their counterreceptors ICAMs on endothelial cells induces PMN arrest due to firm adhesion and Mac-1-dependent crawling. Polarization of PMNs toward the chemoattractant source (i.e., cytoskeletal rearrangement, recruitment of regulators of Arfs, and activation of PI3Kγ, Arf1, and NADPH oxidase at the leading edge) initiates directional sensing and transmigration across the vascular endothelium. PMNs are guided by the gradient of chemoattractant factors and after arriving at the site of infection or tissue injury, the cells initiate phagocytosis or NETosis to kill pathogens and remove cellular debris. PMN granules are schematically represented by colored circles. (b) Signalling pathways downstream of GPCRs, Fcγ receptor IIA (FcγRIIA), and β₂ integrins by which Arfs and their regulators are thought to regulate PMN functional responses are presented schematically. Green arrows indicate direct activation either through lipid-protein or through protein-protein interactions, and negative feedback mechanisms are highlighted in red. Where direct interactions have not been established and/or the signalling mechanisms are unclear, lines are dotted. Cross talk between Arf and Rho family GTPases mediated by ARAP3 and the p21 protein- (Cdc42/Rac-) activated kinase 1 (PAK1)/PAK-interacting Exchange Factor alpha (αPIX) signalling complex is also shown.

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