Alarmin(g) news about danger

Introduction During evolution, multicellular organisms have developed mechanisms to counteract life-threatening events, such as infections and tissue injury, as well as to restore tissue homeostasis. These mechanisms are called ‘the inflammatory response’. To initiate an appropriate inflammatory response, organisms have developed ways to recognize potentially life-threatening events. Danger signals—the molecules that alert the innate immune system and trigger defensive immune responses—have been classically defined as exogenous, pathogen-associated molecular pattern (PAMP) molecules. PAMPs—for example, lipopolysacharide (LPS), viral RNA and bacterial petidoglycans—interact with dedicated receptors on immune cells, the so-called pattern recognition receptors (PRRs). On ligation, PRRs transduce activation signals that lead to the production of proinflammatory molecules such as tumour necrosis factor (TNF). A well-known family of PRRs is the toll-like receptor (TLR) family in which each member recognizes a specific set of PAMPs. However, several endogenous molecules also initiate inflammatory responses by interacting with signalling receptors; such innate danger signals are known as endokines and/or alarmins. The term endokine reflects the potential of these molecules with intranuclear and/or intracellular functions also to act extracellularly, in this case to be immunostimulatory on their release from necrotic cells. The endokine family includes high-mobility-group box (HMGB) proteins, interleukins such as IL-1 , cytosolic calcium-binding proteins of the S100 family, heat-shock proteins (HSPs) and nucleosomes. The term alarmin, coined by J. Oppenheim (Frederick, MD, USA) and co-workers, denotes an array of structurally diverse multifunctional host proteins that are rapidly released during infection or tissue damage, and that have mobilizing and activating effects on receptor-expressing cells engaged in host defence and tissue repair. Innate-immune mediators that have alarmin function include defensins, eosinophilderived neurotoxin, cathelicidins and HMGB1 (Oppenheim & Yang, 2005). During this EMBO workshop in Milan, 120 participants debated innate danger signal biology. A specific focus of the meeting was HMGB1, a nuclear protein that has been known both as an endokine and as an alarmin. Extracellularly released HMGB1 induces inflammation, proliferation and the migration of cells. All these aspects of HMGB1 biology were discussed during the meeting and compared with other known endokines and alarmins such as IL-1 , S100 proteins, HSPs, uric acid, anti-bacterial peptides and hepatoma-derived growth factor (HDGF). An important issue that emerged at the meeting is the likelihood that the activating effect of several alarmins, such as HMGB1 and HSPs, might be due to their propensity to form complexes with molecules derived from microbial organisms or necrotic cells. This might reflect the pathophysiological ways by which these molecules act on TLRs as Department of Medicine, Rheumatology Unit, Karolinska Institutet CMM L8:04, Karolinska Hospital, S-171 76 Stockholm, Sweden San Raffaele Scientific Institute, DIBIT, Chromatin Dynamics Unit, via Olgettina 58, 20132 Milano, Italy Corresponding author. Tel: +46 8 5177 6746; Fax: +46 8 5177 5562; E-mail: [email protected]