Sensing necrotic cells.

Multicellular organisms have developed ways to recognize potentially life-threatening events (danger signals). Classically, danger signals have been defined as exogenous, pathogen-associated molecular patterns (PAMPs) such as bacterial cell wall components (e.g., lipopolysaccharide and peptideglycan) or viral DNA/RNA. PAMPs interact with dedicated receptors on immune cells, so-called pattern recognition receptors (PRRs) and activate immune systems. A well-known family of PRRs is the toll-like receptors (TLRs) in which each member recognizes a specific set of PAMPs. However, not only exogenous pathogens but also several endogenous molecules released from necrotic cells (damaged self) also activate immune systems. These endogenous adjuvants are called damage-associated molecular patterns (DAMPs). It has been reported that high-mobility group box 1 protein (HMGB1), uric acid, heat shock proteins (HSPs) and nucleotides act as endogenous adjuvants. DAMPs are recognized by specific receptors (danger receptors) expressed mainly on antigen-presenting cells such as dendritic cells and macrophages and induce cell maturation and the production of inflammatory cytokines by activating the NF-kB pathway. In this chapter, we will review danger signals released from necrotic cells and its recognition receptors.