Reverse migration

Neutrophil clearance is a prerequisite for inflammation resolution and can be achieved not only by apoptosis and the removal of neutrophil corpses by macrophages, but also by the movement of viable neutrophils away from sites of inflammation; a process defined as reverse migration.

The zebrafish is an ideal model for studying this process in vivo in real time. Using a transgenic line expressing the photoconvertible protein ‘Kaede’ in neutrophils, we can track the behaviour of specific populations of neutrophils during the course of inflammation. For example, if we photocovert neutrophils that have recruited to the wound by 6 hours post injury (the peak of inflammation), we can visualise their migration dynamics during the resolution of inflammation.

We have shown that hypoxia can regulate reverse migration in zebrafish, as genetic or pharmacological activation of Hypoxia-inducible factor-1α (Hif-1α) delays resolution, predominantly by causing increased neutrophil retention at the wound.

We have also identified a compound, Tanshinone IIA, which accelerates inflammation resolution by increasing neutrophil reverse migration. We are currently dissecting the mechanisms that regulate this process, with the idea that targeting endogenous pathways to promote reverse migration will be a new avenue in the development of more effective treatments for inflammatory disease.