Danger signals: a time and space continuum

Sudden uncontrolled necrosis and the controlled, physiological process of apoptosis are considered to be distinct forms of cell death. Necrotic cell death is associated with the release of danger signals, the consequent maturation of professional antigen-presenting cells (dendritic cells) and the priming of immune responses, whereas apoptotic cell death is associated with the induction of tolerance. Recently, uric acid in necrotic cell lysates, in addition to other substances, has been identified as a danger signal for dendritic cells. We discuss the significance and principle of action of these molecules in alerting the immune system to dying cells and propose that, in sterile injury, they have a primary initiating role, whereas in the presence of pathogens, initiation is caused by pathogen-associated molecules.