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

Abstract

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.

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…It remains unknown whether differences in splice variants between humans and mice [23] might also influence ligand specificity in different diseases. Thus, the postulated promiscuity of RAGE, which would make it potentially able to bind almost damage-associated molecular patterns [24], does not in fact exist, since post-translational modifications affect the relative specificity of a given ligand in a given situation of cellular activation.…”

Transcriptional Regulation of the Endogenous Danger Signal Tenascin-C: A Novel Autocrine Loop in Inflammation

“…As such, these danger signals are key targets in preventing inappropriate inflammation (reviewed in Refs. [12][13][14]. However, the molecular mechanisms that regulate tissue levels of endogenous danger signals remain unclear.…”

S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll‐like receptor 4: Implications for bone destruction in murine antigen‐induced arthritis

“…Recently, S100A8 and the S100A8/A9 complex were identified as endogenous ligands of Toll-like receptor 4 (TLR-4) (12). TLRs belong to the family of pattern recognition receptors, recognizing both exogenous pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, to which the alarmins S100A8 and S100A9 belong (13).…”