Characterising neutrophil reverse migration using wet and dry experimentation

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Neutrophils are the predominant type of leukocyte in humans and form an integral part of the innate immune system. Upon activation, they move to the site of infection or injury, following gradients of chemokines in a process called chemotaxis. Once there, they perform effector functions (e.g. phagocytosis, release of ROS) before dying by apoptosis. Neutrophil reverse migration, or retrograde chemotaxis, is the movement away from the site of infection or injury and opposite to the attracting chemokine gradient. It has been described in vitro and in vivo, and is contrary to existing dogma of neutrophil behaviour. The process may be involved in inflammation resolution, but has been shown to have a pathologic aspect, promoting inflammation at distal sites such as the lungs. It is thought it could be implicated in chronic inflammatory diseases such as rheumatoid arthritis and COPD.This project will investigate the molecular mechanisms controlling neutrophil reverse migration by combining computational modelling with wet lab methods. Basal and post-migrated neutrophils will be examined using bespoke chemotaxis assays optimised for this project. Their chemotactic behaviour and differential chemokine and receptor expression will be compared. Computational modelling will be used to find and expand ways in which metabolism of chemokines and other attractive molecules can turn them from attractants into repellents and be used to define more informative experimental set-ups, the results of which will in turn be used to test and further refine the model. There are several possibilities to be addressed: Does chemoattractant break-down mediate reverse migration? Do chemoattractants turn into chemorepellents? Does reverse migration involve receptor desensitization? Do neutrophils change once they have been recruited to a site of infection? This project will work towards identifying how neutrophil reverse migration could be therapeutically targeted.