Mechanisms of Disease: a 'DAMP' view of inflammatory arthritis

Damage-associated molecular pattern molecules, such as heat shock proteins and S100 proteins, represent tissue danger signals, which mediate inflammatory responses after being released from activated or necrotic cells. These danger signals, and their receptors, could be targets for novel approaches in the treatment of rheumatic diseases, as discussed in this article. Innate immunity achieves our primary host defense by recognizing invading microorganisms through pathogen-associated molecular patterns (PAMPs) and by reacting to tissue damage signals called damage-associated molecular patterns (DAMPs). DAMP molecules, including high mobility group box 1 protein (HMGB-1), heat-shock proteins (HSPs), uric acid, altered matrix proteins, and S100 proteins, represent important danger signals that mediate inflammatory responses through the receptor for advanced glycation end-products (RAGE, also known as AGER) and Toll-like receptors, after release from activated or necrotic cells. The terms 'alarmins' and 'endokines' have also been proposed for DAMP molecules. A prototypic DAMP molecule, the nuclear protein HMGB-1, is either passively released by necrotic cells or actively secreted with delay by activated cells. S100A8, S100A9, and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes. They are rapidly secreted by activated monocytes or neutrophils, which are abundant in inflamed synovial tissue. HSPs are involved in the crosstalk between innate and adaptive immune systems, and primarily mediate immune regulatory functions. Multiple positive feedback loops between DAMPs and PAMPs and their overlapping receptors temporally and spatially drive these processes and may represent the molecular basis for the observation that infections, as well as nonspecific stress factors, can trigger flares in rheumatic diseases. Key Points The innate immune system, as well as the adaptive immune system, has a key role in initiating and perpetuating synovial inflammation by responding to groups of macromolecules that represent a recognition pattern for potential threats to the host Owing to their similarities to cytokines and their release by activated or damaged cells under conditions of cell stress, the terms 'endokines', 'alarmins', or 'danger signals' have been used as synonyms for proinflammatory damage-associated molecular pattern molecules (DAMPs) DAMPs include high mobility group box 1 protein (HMGB-1), heat-shock proteins, uric acid, altered matrix p