The ACKR2-CCR2 axis in development and disease.

The movement of white blood cells (leukocytes) into and within tissues is regulated by specialised proteins called chemokines. Chemokines are produced by a range of cells and tissues and interact with molecules called receptors on the leukocytes. Therefore, for example, when a tissue becomes inflamed or infected it produces chemokines which then attract leukocytes to the inflamed sites. These leukocytes then kill invading bacteria and viruses and help to repair the damaged tissue. Chemokines are therefore extremely important biological regulators. The downside of chemokines, and their receptors, is that they are also involved in attracting leukocytes to previously healthy tissue sites to give rise to, what are called, autoimmune and inflammatory diseases. So, for example, in rheumatoid arthritis leukocytes are attracted inappropriately to joints and once there, instead of killing bacteria, they start to kill the tissue and cause profound problems for the patients. Chemokines and their receptors are therefore important targets for therapy. We have a particular interest in molecules called 'atypical chemokine receptors'. These molecules fine-tune chemokine-driven responses and are involved in the regulation of leukocyte positioning within tissues. This proposed Programme of work relates specifically to one of these atypical chemokine receptors which is called ACKR2. ACKR2 destroys the chemokines which are involved in inflammation and it is therefore a 'negative regulator' of inflammatory responses. We have implicated it in a wide range of human inflammatory pathologies and have shown that it is essential for the resolution of the inflammatory response. In the current Programme Grant we propose to use basic scientific, and clinically focused, approaches to try to analyse the functions of ACKR2 in more detail. This is of importance as it will enhance our understanding of the overall orchestration of chemokine function and will provide novel potential therapeutic targets. Specifically, in this Programme, we propose to examine novel roles for ACKR2 in the regulation of what is called the lymphatic system. This system is essential for the drainage of fluid from our tissues and is also an indispensable contributor to the development of immune responses. Data that we have generated so far indicate that ACKR2 is involved in establishing networks of lymphatic vessels and we propose to examine this in considerable detail. We will define the biological mechanisms behind this as well as the functional and pathological implications. Secondly the Programme will focus on new observations that we have made concerning the involvement of ACKR2 in the process of metastasis. Metastasis is frequently the terminal stage of cancer and it is metastasis that kills the vast majority of cancer patients. Mice that lack ACKR2 basically do not develop metastasis and we now propose to try to examine the mechanisms behind this. We also suggest that these data highlight ACKR2 as a potential therapeutic target for use in treating human metastasis. We will therefore generate compounds capable of inhibiting ACKR2 function and will test these in various models of metastasis.