The Mechanisms Controlling Neutrophil Migration

Neutrophil accumulation in the lung plays a significant role in the pathogenesis of inflammatory respiratory diseases including cystic fibrosis and COPD. The entry of neutrophils into the lung has been well characterised. However, the fate of these cells once inside the tissue microenvironment of the lung is not fully understood. An understanding of the interaction and signal transduction pathways controlling the migration of neutrophils within the lung could prove beneficial in the treatment of respiratory diseases. A variety of signal transduction pathways have been suggested to be involved in neutrophil migration. We aimed to determine the mechanisms controlling chemokinetic and chemotactic neutrophil migration in response to stimulation with CXCL8 and GM-CSF. Stimulation with CXCL8 in the 3D collagen migration assay caused a concentration dependent migration which, depending on the assay used can be chemokinetic (non-gradient) or chemotactic (gradient). Stimulation with GM-CSF caused a concentration dependent chemokinetic migration. Both chemokinetic and chemotactic migration induced by CXCL8 signal via a GPCR. Chemokinetic migration in response to stimulation with both CXCL8 and GM-CSF is dependent on the mitogen activated protein kinase, ERK and the PI3-Kinases and is partially dependent on ROCK. Chemotactic migration in response to stimulation with CXCL8 is dependent on the PI3-Kinases and partially dependent on ERK. Further exploration of the specific class I PI3-Kinases highlighted that although both chemokinesis and chemotaxis are dependent on PI3-Kinase delta, there is a differential requirement for the PI3-Kinase alpha and gamma isoforms. Chemokinesis is dependent on the PI3-Kinase gamma isoform whereas chemotaxis is dependent on the PI3-Kinase alpha isoform. In conclusion, this study highlights the similarities and differences between the signal transduction pathways needed for neutrophil chemokinesis and chemotaxis, in response to stimulation with CXCL8 and GM-CSF. Further examination of the mechanisms controlling neutrophil migration could be valuable in the treatment of conditions characterised by neutrophil influx.