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The role of chemokine receptor trafficking in regulating neutrophil migration to inflammatory sites



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Coombs, Caroline Gisele 


Neutrophils are the first immune cells to be recruited to sites of tissue injury or infection. Upon detection of an inflammatory stimulus, neutrophils exit the vasculature and migrate directionally through the interstitial tissue towards the target site. Once at the target site, neutrophils may either focalise and form clusters or may exhibit a more dispersive and exploratory behaviour. Focalisation acts to concentrate local neutrophil effector responses but excess clustering can prove detrimental, resulting in undesirable tissue damage. Neutrophil dispersal promotes the encounter of alternative signals and therefore drives resolution of the response. A fine balance between focalisation and exploration must exist to ensure that the inflammatory response is effective but also transient and self-resolving.  Neutrophils are recruited to target sites by gradients of attractant molecules, a major class of which is chemokines. Chemokines bind to G-protein coupled receptors (GPCRs) and initiate complex intracellular signalling cascades which ultimately result in directional neutrophil migration. Upon ligand binding, GPCRs can undergo multiple trafficking fates which may in turn influence sensitivity to the gradient. However, the functional significance of receptor trafficking during neutrophil responses in vivo remains unknown. Here, I address this question using zebrafish Cxcl8a (a homologue of human CXCL8) which signals through two G-protein coupled receptors, Cxcr1 and Cxcr2. Through new in vivo biosensors, I show that Cxcr1 and Cxcr2 exhibit differential trafficking in response to endogenous gradients. Cxcr1 is extensively internalised whilst Cxcr2 is sustained on the cell membrane. Live-imaging of receptor knockout neutrophils revealed that Cxcr1 promotes neutrophil clustering at wounds, whilst Cxcr2 drives dispersal. Through receptor mutagenesis I show that neutrophil dispersal relies on Cxcr1 internalisation and membrane sustenance of Cxcr2. Thus, I show that differential trafficking of two receptors balances the rise and fall of neutrophil inflammatory responses. To my knowledge, this is the first study to functionally link receptor dynamics to neutrophil migration behaviour in vivo.





Sarris, Milka


Neutrophil, Chemokine, Zebrafish, Cxcr1, Cxcr2, Cxcl8, Receptor, GPCR, Inflammation, Migration


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
MRC 3-year studentship