Macrophage provenance, proliferation and plasticity in nematode infection

Macrophages are white blood cells (WBC) involved in killing microbes but also have important roles in repairing damaged tissue. Macrophages that are activated by the immune system to kill bacteria are called 'classically activated macrophages'. However, during infection with large migrating worms, macrophages take on an 'alternative' activation state. Alternatively activated macrophages (AAM) are induced by interleukin-4, an immune molecule that is induced by worm infection and other conditions such as allergy. AAM have important roles in repairing damaged tissue, but how they effect worms that live in the tissues is not known. We are particularly interested in filarial worms that cause debilitating diseases like elephantiasis and river blindness. During infection with either microbes or worms our bodies mount an inflammatory response, in which large numbers of macrophages accumulate at the site of infection. It has always been presumed that the increase in macrophage numbers during an inflammatory response was caused by recruitment of WBC that are made in bone marrow and circulate in the blood. While investigating the killing of filarial worms in the body tissues, we made a major discovery. We found that the big increase in macrophage numbers at the site of worm infection can occur without recruitment of cells from the blood because locally resident macrophages rapidly divide within the tissues. We have shown that that the main factor leading to macrophage cell division is interleukin-4, the same factor that induces AAM. We believe this new form of inflammation may be less damaging to the tissues, and more suited to repairing damage. However, we don't know whether it contributes to worm killing or helps worms to survive. We were recently able to demonstrate that macrophages are important in killing worms but we don't know how. We want to investigate whether macrophages that come in from the blood or macrophages that divide locally are better at killing worms. However, our discovery that macrophages can be generated by local cell division is so new that many other fundamental questions need to be addressed as well. So the major aims of this proposal are: What controls macrophage division during worm infection? Do macrophages that come in from the blood have different functions than macrophages which divide locally? What are the consequences for worm infection of blocking macrophage division or blocking their ability to become alternatively activated? How does cell division vs. recruitment from the blood effect the ability of macrophages to switch between alternative and classical activation states and how does this effect situations in which an individual is infected with both worms and bacteria? The results of these studies are important for many reasons. First, we need to know how worms are killed so we can develop better treatment strategies and vaccines. Secondly, understanding more about the function of locally dividing macrophages vs. macrophages that come in from the blood, is relevant to almost all inflammatory conditions. Currently, treatment for most inflammatory diseases is targeted at preventing recruitment of macrophages, or enhancing their clearance. The contribution (good or bad) of the locally dividing population has not been investigated. Finally, many diseases such as cancer, are treated with drugs that block cell division but we don't know what effect that might have on local macrophage function. We believe the interleukin-4-driven immune response that involves AAM and local marcrophage division is an evolutionary ancient means to cope with large and damaging parasites without minimal self damage. By understanding these evolutionarily ancient pathways we can shed light on modern inflammatory diseases as well as important infectious diseases of the tropics.