Damage-associated molecular patterns (DAMPs), also known as danger-associated molecular patterns, danger signals, and alarmin, are host biomolecules that can initiate and perpetuate a noninfectious inflammatory response. In contrast, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response. A subset of DAMPs are nuclear or cytosolic proteins. When released outside the cell or exposed on the surface of the cell following tissue injury, they move from a reducing to an oxidizing milieu, which results in their denaturation. Also, following necrosis (a kind of cell death), tumor DNA is released outside the nucleus, and outside the cell, and becomes a DAMP.
Two papers appearing in 1994 presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first came from transplant surgeons who conducted a prospective randomized double-blind placebo-controlled trial. Administration of recombinant human superoxide dismutase (rh-SOD) in recipients of cadaveric renal allografts demonstrated prolonged patient and graft survival with improvement in both acute and chronic rejection events. They speculated that the effect was related to its antioxidant action on the initial ischemia/reperfusion injury of the renal allograft, thereby reducing the immunogenicity of the allograft and the "grateful dead" or stressed cells. Thus free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses.
The second suggested the possibility that the immune system detected "danger", through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues. Thus these two papers together presaged the modern sense of the role of DAMPs and redox reviewed here, important apparently for both plant and animal resistance to pathogens and the response to cellular injury or damage. Although many immunologists had earlier noted that various "danger signals" could initiate innate immune responses, the "DAMP" was first described by Seong and Matzinger in 2004.
DAMPs vary greatly depending on the type of cell (epithelial or mesenchymal) and injured tissue. Protein DAMPs include intracellular proteins, such as heat-shock proteins or HMGB1 (high-mobility group box 1), and proteins derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments. Examples of non-protein DAMPs include ATP, uric acid, heparin sulfate and DNA.
The chromatin-associated protein high-mobility group box 1 (HMGB1) is a prototypical leaderless secreted protein [LSP] secreted by hematopoietic cells through a lysosome-mediated pathway. It is a major mediator of endotoxin shock and acts on several immune cells to trigger inflammatory responses as a DAMP. Known receptors for HMGB1 include TLR2, TLR4 and RAGE (receptor for advanced glycation endproducts). HMGB1 can induce dendritic cell maturation via upregulation of CD80, CD83, CD86 and CD11c, induce production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8) as well as upregulate expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells.
DNA and RNA
The presence of DNA anywhere other than the nucleus or mitochondria is perceived as a DAMP and triggers responses mediated by TLR9 and DAI that drive cellular activation and immunoreactivity. Interestingly, some tissues such as the gut are inhibited by DNA in their immune response (this needs a reference, and may be a misinterpretation of what the gut does). Similarly, damaged RNAs released from UVB-exposed keratinocytes activate TLR3 on intact keratinocytes. TLR3 activation stimulates TNF-alpha and IL-6 production, which initiate the cutaneous inflammation associated with sunburn.
S100 is a multigenic family of calcium modulated proteins involved in intracellular and extracellular regulatory activities with a connection to cancer as well as tissue, particularly neuronal, injury.
Nucleotides (e.g., ATP) and nucleosides (e.g., adenosine) that have reached the extracellular space can also serve as danger signals by signaling through purinergic receptors. ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death. Extracellular ATP triggers mast cell degranulation by signaling through P2X7 receptors. Similarly, adenosine triggers degranulation through P1 receptors. Uric acid is also an endogenous danger signal released by injured cells.
Mono and polysaccharides
The ability of the immune system to recognize hyaluronan fragments is one example of how DAMPs can be made of sugars.
Clinical targets in various disorders
Theoretically, the application of therapeutics in this area to treat disorders as arthritis, cancer, ischemia-reperfusion, myocardial infarction and stroke could include options as:
- Preventing DAMP release [proapoptotic therapies; platinums; ethyl pyruvate];
- Neutralizing or blocking DAMPs extracellularly [anti-HMGB1; rasburicase; sRAGE, etc.];
- Blocking the DAMP receptors or their signaling [RAGE small molecule antagonists; TLR4 antagonists; antibodies to DAMP-R].
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