Recognition and removal of apoptotic cells
Apoptosis, or programmed cell death, occurs at high rates in infected, inflamed or remodelling tissue. Free apoptotic cells are rarely found in tissue, even during inflammation, as they are rapidly removed by either local nonprofessional phagocytes or specialised phagocytes. Our previous work and work of other groups have demonstrated that such clearance has significant regulatory effects on inflammatory and immune responses. We have shown that uptake of apoptotic cells inhibits the subsequent maturation of DCs, reducing the upregulation of costimulatory molecules, blocking the production of IL12 and decreasing the capacity of DCs to stimulate T cell proliferation. We have also shown that macrophages are primed for inflammatory responses immediately following apoptotic cell uptake, but this is then converted to a reparative resolving response. We have proposed that interaction of phagocytes with apoptotic cells leads to a qualitatively different inflammatory and immune response from interaction with foreign agents or pathogens. Macrophages are reprogrammed to stimulate rapid reparative inflammatory responses without the involvement of the adaptive immune system. DC maturation is inhibited, downregulating responses to apoptotic cell-derived self antigen and contributing to the maintenance of self tolerance. For further investigation of this process we have focussed on mechanisms by which we can manipulate the molecules involved in recognition, phagocytosis and response to apoptotic cells and foreign agents, and in these studies we have concentrated on the alpha(v) integrin family. Through generation of alpha(v) conditional knockout mice we are able to selectively inhibit apoptotic cell uptake in different organs and at different times and look at the consequences for the immune system.