91Ö±²¥

Lay summary

Immune cells play an important role in the normal development, general upkeep and repair of our bodies, in addition to their roles defending against infection and disease. An important function of a subset of our white blood cells (called macrophages) is to detect, ingest (phagocytose) and degrade debris, dying cells and invading pathogens.

When these processes go wrong it can cause or worsen a wide range of human diseases and conditions including autoimmunity, atherosclerosis, cancer and chronic inflammation, often due to the inappropriate behaviour of the macrophages themselves. A major problem is that we do not fully understand how the function of macrophages is controlled; understanding this would enable the generation of therapies aimed at manipulating macrophage behaviour and so prevent or reduce their contribution to these damaging conditions.

Fruit flies (Drosophila) are considerably simpler than vertebrates such as ourselves, yet the key genes important in macrophage function are also present. This makes it much easier for us to study and identify new genes involved in macrophage functions such as migration, phagocytosis and degradation of ingested material.

Importantly, fruit flies contain a population of cells called hemocytes that are very similar in their function and behaviour to our own macrophages. We study these fly macrophages to understand new mechanisms by which our own immune cells may be controlled.

Contact with cells undergoing a programmed form of death (called apoptosis), which often occurs at sites of injury or pathology, is thought to alter the behaviour of macrophages. This can be helpful in some circumstances but on other occasions it may cause macrophages to contribute to disease progression.

Drosophila hemocytes display altered responses when challenged in the presence of increased levels of cell death. One key area in our lab is to use fruit flies as a model system to understand how apoptotic cells regulate macrophage function. We are also interested in understanding how engulfment of other cargoes is controlled and regulates macrophage behaviour (e.g. pathogenic bugs).

Technical summary

Drosophila hemocytes are a population of highly migratory macrophages that disperse over the entire embryo during development. They represent the cellular arm of the innate immune system in the fly and clear both apoptotic cells and pathogens - without these functions development or survival in the face of infection are strongly perturbed, respectively.

The unparalleled imaging capabilities of hemocytes within the developing embryo, coupled with the well-established and rapid genetics of Drosophila, enable the cell biology underlying macrophage function to be determined in the context of an intact organism.

Clearance of apoptotic cells is crucial for development and this process is known to alter macrophage function. Undigested apoptotic corpses within hemocytes can suppress both their general motility and inflammatory responses. Using this model system we are studying how apoptotic corpses affect macrophage behaviour at a number of stages during the process of apoptotic cell clearance.

We are particularly focused on how the stages post-engulfment can inhibit the migratory machinery of hemocytes. This mechanism could have important consequences for a wide range of human diseases, since it could contribute to the inappropriate or prolonged localisation of macrophages at the numerous sites of pathology that contain high levels of cells dying by apoptosis.

We have established a number of collaborations with groups within the Medical School and Biomedical Science at the University of 91Ö±²¥ in order to translate our findings into other vertebrate systems (Zeidler, Prince and Johnston Labs).

Current Projects:

• Anti-inflammatory signalling in Drosophila macrophages.
• Impact of apoptotic cell clearance on inflammatory responses.
• Find-me cue signals in vivo.
• Blood cell proliferation and activation.
• Macrophage subtypes in health and disease.