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Title: Regulation of inflammation by differential neutrophil migration patterns in zebrafish
Author: Isles, Hannah
ISNI:       0000 0004 7428 2549
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Current treatments for chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF) are non-specific and generally ineffective, thus the need to identify novel targets to develop more effective clinical treatments is essential. The excessive tissue damage characteristic of respiratory chronic inflammatory diseases is caused by the inappropriate retention of neutrophils in the lungs, however the underlying mechanisms are not fully understood. The identification of novel neutrophil migration patterns including neutrophil swarming and reverse migration add complexity to the modulation of neutrophil migration and retention within inflamed tissue, the precise molecular mechanisms of which remain to be fully elucidated. Here I used a zebrafish model of spontaneously resolving inflammation to study the effect of differential neutrophil migration on the outcome of inflammation. I aimed to characterise the neutrophil swarming response and investigate the initiation of swarming by cell death signalling. Furthermore I investigated the hypothesis that the CXCR4/CXCL12 signalling axis generates a neutrophil retention signal at the wound site. Inflammation was induced in larvae by tail-fin transection and differential neutrophil migration patterns were observed using transgenic reporter zebrafish lines. CXCR4/CXCL12 signalling was inhibited using the compound AMD3100 which was administered by injection or incubation. Here I identified that neutrophil swarming occurs following the migration of neutrophils to the wound site in three distinct phases. I demonstrated that swarms are initiated by 'pioneer' neutrophils and began to investigate cell death in the context of swarm initiation. Zebrafish neutrophils predominantly express the Cxcr4b receptor, whose ligand Cxcl12a is detected at the wound site in injured larvae. Pharmacological inhibition of CXCR4 accelerates inflammation resolution by accelerating neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signalling may play an important role in neutrophil retention at sites of inflammation, and provides one of the first attempts at characterising the neutrophil swarming response. Furthermore this work has formed the basis for future studies to dissect a role for CXCR4/CXCL12 signalling in inflammation resolution through the modulation of neutrophil swarm resolution.
Supervisor: Renshaw, Stephen ; Elks, Phillip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available