Macrophage programming in inflammatory disease
Before embarking on the work presented here I showed that certain activating signals, such as IFN-gamma and TNF-alpha programmed macrophages to develop distinct sets of properties in vitro, which included unresponsiveness to other types of activation. This raised the question whether macrophage programming occurs in passive and active renal inflammation and whether the macrophage programme could be biased by systemic administration of cytokines. The data presented here shows that macrophages infiltrating acutely inflamed glomeruli of rats with nephrotoxic nephritis display programmed behaviour: operationally they behave as though programmed by IFN-gamma, and maintain these characteristics despite systematic administration of anti-inflammatory cytokines such as IL-4 or TGF-beta. This triggered further studies using a model of mesangioproliferative nephritis that can be adapted to induce resolving or progressive glomerular injury. These show that glomerular localisation does not always induce macrophage programming and that whether macrophages become programmed or not depends on the nature of the injury. Furthermore the data shows that macrophages become committed to a particular programme shortly after entering a programming environment. These observations raise question about the factors that induce macrophage programming at early stages of inflammatory disease and its consequences for its outcome. It provides an important mechanistic insight into how macrophage functional development is influenced by the underlying disease process.