Screening for, and characterisation of, novel immune cell extravasation genes in Drosophila, mice and man

An inflammatory response is pivotal in many normal physiological responses, for example wherever there is a wound or site of infection. In such scenarios, if inflammation is delayed or insufficient then the consequences to health can be catastrophic. Conversely, if the inflammatory response is excessive or slow to resolve, then 'chronic' inflammation can also lead to several pathologies, ranging from tissue scarring through to atherosclerosis or even cancer. A better understanding of how inflammatory cells are recruited to their target tissues will help guide us how the inflammatory response might be modulated therapeutically to treat these conditions.

One of the key 'rate-limiting' steps in an inflammatory response is the movement of leukocytes (white blood cells) from the circulation across blood vessel walls (known as 'extravasation') to sites of damage or infection. However, despite decades of research in this field, many aspects of this step in leukocyte recruitment remain poorly understood and there is still much to learn; this is in part because breaching of vessel walls is a highly complex process to dissect at the molecular level and it is incredibly difficult to image in opaque tissues of traditional mammalian models (e.g. mouse).

In Bristol we have recently developed a new model in which to study immune cell 'extravasation' using the fruitfly, Drosophila. Fruitflies offer many advantages for this research, being genetically 'tractable' (easy to mutate and study individual genes) and also translucent (enabling us to watch these movements live using microscopy). Since fruitflies largely have an 'open circulation' without discrete blood vessels, they were not previously considered a useful model for this field. However, we have identified a period in pupal life when immune cells circulate through the wing "veins" and a laser-induced wound triggers immune cells to leave the veins and move towards the damage. We have already used this model to identify one...