Complexity of danger: the diverse nature of damage-associated molecular patterns

Abstract

In reply to internal or external danger stimuli, the body orchestrates an inflammatory response. The endogenous triggers of this process are the damage-associated molecular patterns (DAMPs). DAMPs represent a heterogeneous group of molecules that draw their origin either from inside the various compartments of the cell or from the extracellular space. Following interaction with pattern recognition receptors in cross-talk with various non-immune receptors, DAMPs determine the downstream signaling outcome of septic and aseptic inflammatory responses. In this review, the diverse nature, structural characteristics, and signaling pathways elicited by DAMPs will be critically evaluated.

Keywords: ATP; Autophagy; Biglycan; Decorin; Heat Shock Protein (HSP); Heparan Sulfate; Hyaluronan; Inflammasome; Necrosis (Necrotic Death); Small Leucine-rich Proteoglycan (SLRP); Toll-like Receptor (TLR).

FIGURE 1.

Cell- and ECM-derived DAMPs activate TLRs and inflammasome. Following cell death or injury, various intracellular DAMPs are released extracellularly from mitochondria, the autophagosome, the nucleus, and the cytosol. In turn, HMGB1, histones, HSPs, and S100 proteins target the cell surface TLRs. mtDNA activates the intracellular TLRs following endocytosis. In addition, histones and uric acid activate the inflammasome following phagocytosis, whereas ATP activates the inflammasome in a P2X₇-dependent manner. Alternatively, tissue injury or stress determines the release of various ECM-derived DAMPs as a consequence of proteinase activity. Thus, SLRPs (biglycan, decorin), HA, and HS trigger cell surface TLRs activation. In addition, the SLRP biglycan activates the inflammasome via the P2X₇ receptor. In contrast, HA is internalized in a CD44-dependent manner, and after fragmentation into HA-oligosaccharides, activates the inflammasome.