Damage-associated molecular pattern

Two papers appearing in 1994 presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first[6] 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[7] 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.[1]

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[8] or HMGB1[9], and materials derived from the extracellular matrix that are generated following tissue injury, such as hyaluronan fragments.[10]

- Non-protein DAMPs include ATP,[11][12] uric acid,[13] heparin sulfate and DNA.[5]

1. Protein DAMPs

(1) HMGB1 : HMGB1 (High-mobility group box 1), a member of the HMG protein family, is a prototypical chromatin-associated LSP (leaderless secreted protein), secreted by hematopoietic cells through a lysosome-mediated pathway.[14] HMGB1 is a major mediator of endotoxin shock[15] and is recognized as a DAMP by certain immune cells, triggering an inflammatory response.[9] It is known to induce inflammation by activating NF-kB pathway by binding to TLR, TLR4, TLR9, and RAGE (receptor for advanced glycation end products).[16] HMGB1 can also induce dendritic cell maturation via upregulation of CD80, CD83, CD86 and CD11c, and the production of other pro-inflammatory cytokines in myeloid cells (IL-1, TNF-a, IL-6, IL-8), and it can lead to increased expression of cell adhesion molecules (ICAM-1, VCAM-1) on endothelial cells.[17]

(2) 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. 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.[18]

(3) S100 proteins : 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.[19][20][21][22][23][16] Their main function is the management of calcium storage and shuffling. Although they have various functions, including cell proliferation, differentiation, migration, and energy metabolism, they also act as DAMPs by interacting with their receptors (TLR2, TLR4, RAGE) after they are released from phagocytes.[2]

(4) Mono and polysaccharides : The ability of the immune system to recognize hyaluronan fragments is one example of how DAMPs can be made of sugars.[24]

2. Non-protein DAMPs

- Purine metabolites : 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.[25] ATP and adenosine are released in high concentrations after catastrophic disruption of the cell, as occurs in necrotic cell death.[26] Extracellular ATP triggers mast cell degranulation by signaling through P2X7 receptors.[27][25][28] Similarly, adenosine triggers degranulation through P1 receptors. Uric acid is also an endogenous danger signal released by injured cells.[24] Adenosine triphosphate (ATP) and uric acid, which are purine metabolites, activate NLR family, pyrin domain containing (NLRP) 3 inflammasomes to induce IL-1β and IL-18.[2]

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].

1. DAMPs can be used as biomarkers for inflammatory diseases and potential therapeutic targets. For example, increased S100A8/A9 is associated with osteophyte progression in early human OA (osteoarthritis), suggesting that S100 proteins can be used as biomarkers for the diagnosis of the progressive grade of OA. Furthermore, DAMP can be a useful prognostic factor for cancer. This would improve patient classification, and a suitable therapy would be given to patients by diagnosing with DAMPs. The regulation of DAMPs signaling can be a potential therapeutic target to reduce inflammation and treat diseases. For example, administration of neutralizing HMGB1 antibodies or truncated HMGB1-derived A-box protein ameliorated arthritis in collagen-induced arthritis rodent models. Clinical trials with HSP inhibitors have also been reported. For non-small cell lung cancer (NSCLC), HSP27, HSP70, and HSP90 inhibitors are under investigation in clinical trials. In addition, treatment with dnaJP1, which is a synthetic peptide derived from DnaJ (HSP40), had a curative effect in RA (rheumatoid arthritis) patients without critical side effects. Taken together, DAMPs can be useful therapeutic targets for various human diseases, including cancer and autoimmune diseases.[2]

2. Recent evidence revealed that DAMPs can trigger re-epithelialization upon kidney injury, contributing to epithelial-mesenchymal transition and, potentially, to myofibroblast differentiation and proliferation. Thus, these discoveries suggest that DAMPs drive not only immune injury but also kidney regeneration and renal scarring. For example, TLR2-agonistic DAMPs activate renal progenitor cells to regenerate epithelial defects in injured tubules.Also, TLR4-agonistic DAMPs induce renal dendritic cells to release IL-22, which also accelerates tubule re-epithelialization in AKI[29]. Finally, DAMPs also promote renal fibrosis by inducing NLRP3, which also promotes TGF-β receptor signaling.[30]