Key to images in the banner (left to right):
1) Drosophila embryo with macrophages labelled in green - these have dispersed over the entire embryo from the head (the head is the left of the embryo). If this dispersal fails, the embryo will not hatch to a larva as the macrophages must clear rubbish from areas away from the head and also secrete proteins necessary to hold the tissues together.
2) macrophages (green) migrating along the developing nerve cord on the ventral side of the embryo (down) - the purple staining shows glial cell nuclei, which form part of the nerve cord. If this migration doesn't happen, the nerve cord isn't formed properly.
3) macrophages (green) packed into an epithelial wound in a Drosophila embryo. We introduce these wounds with laser beams! This migration can be used to understand how immune cells migrate to sites of damage and the mechanisms are conserved with vertebrates.
4) a macrophage (green) full of apoptotic/dying cells (purple). Macrophages are needed to clear away dying cells and debris.
All these processes also take place within our bodies and are necessary for our health and development!
1) Drosophila embryo with macrophages labelled in green - these have dispersed over the entire embryo from the head (the head is the left of the embryo). If this dispersal fails, the embryo will not hatch to a larva as the macrophages must clear rubbish from areas away from the head and also secrete proteins necessary to hold the tissues together.
2) macrophages (green) migrating along the developing nerve cord on the ventral side of the embryo (down) - the purple staining shows glial cell nuclei, which form part of the nerve cord. If this migration doesn't happen, the nerve cord isn't formed properly.
3) macrophages (green) packed into an epithelial wound in a Drosophila embryo. We introduce these wounds with laser beams! This migration can be used to understand how immune cells migrate to sites of damage and the mechanisms are conserved with vertebrates.
4) a macrophage (green) full of apoptotic/dying cells (purple). Macrophages are needed to clear away dying cells and debris.
All these processes also take place within our bodies and are necessary for our health and development!
Summary for the non-specialist
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. 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. Therefore we are using this system to try to understand how apoptotic cells regulate macrophage function. |
Gallery - click to see larger images
|
We can induce wounds in the developing embryo and follow the recruitment of fluorescently-labelled macrophages live. This movie shows macrophages (purple) and their rapid movement to a wound. The outside (epithelium) of the embryo is labelled in green. We have used this assay to work out how signals are generated to attract immune cells to sites of damage. We require this migration (inflammatory response) to move immune cells to damaged sites to protect against infection, clear up debris and help remodel tissue during repair. Understanding how these processes are controlled can provide insights into how the inflammatory response in controlled in ourselves (since, owing to the fact we share a common ancestor with flies, many of the genes involved in this process are also present in us). This will hopefully provide new ideas (new genes to target) about how to manipulate inflammatory responses, a crucial endeavour given the range of human diseases affected by inflammation.
|
Movie showing inflammatory migration of Drosophila macrophages to a wound
|
For specialists:
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 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. Migratory responses to induction of apoptosis by GFP-lablled macrophages. Apoptosis is induced in the centre of the field of view.
|
Movie showing dispersal of macrophages through embryonic development. Macrophages labelled via nuclear red stinger.
Lateral migration of GFP-labelled macrophages from the midline - a stereotyped and developmentally-controlled migration.
Wandering migration of macrophages visualised via nuclear red stinger after lateral migration
|