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DAMPening inflammation by modulating TLR signalling.

Piccinini AM, Midwood KS - Mediators Inflamm. (2010)

Bottom Line: However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis.Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation.We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 65 Aspenlea Road, Hammersmith, London W6 8LH, UK.

ABSTRACT
Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

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Related in: MedlinePlus

DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig3: DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.

Mentions: The etiology of many inflammatory and autoimmune diseases is unclear; the initiating stimuli are often not well defined and the reasons why the mechanisms that ordinarily control the immune response fail are not known. However, it is clear that these diseases are characterized by an extremely destructive tissue environment. Accordingly, high levels of DAMPs occur locally and/or systemically in many of these conditions. For example, a wide range of endogenous TLR activators, including heat shock proteins, HMGB1, host DNA, fibrinogen, FNEDA, and tenascin-C, are observed in synovia of RA patients but not in synovia from normal joints or non-inflamed synovia from osteoarthritis (OA) patients [106–112]. High levels of HMGB1 and tenascin-C circulate in the serum of septic patients [113, 114], and high serum concentrations of DNA-containing immune complexes are associated with SLE [46], including nucleosome-HMGB1 complexes [90, 115]. In addition, elevated levels of low MW HA fragments are reported in the bronchial alveolar lavage fluid and serum of patients with inflammatory lung diseases [116–118]. In many cases levels of endogenous TLR activators are indicative of disease activity; elevated levels of extracellular HMGB1 localize specifically to active lesions of multiple sclerosis (MS) patients and correlate with active inflammation [119]. Furthermore, the S100 family of calcium binding proteins have long been reliable biomarkers of inflammation in a wide variety of diseases; for example, both MRP8 and MRP14 levels in the RA synovium and synovial fluid correlate with disease activity to a degree greater than levels of C-reactive protein (reviewed in [120]). Many endogenous TLR activators are also overexpressed in tumor cells. Figure 3 summarises some of the diseases with which endogenous TLR activators are associated.


DAMPening inflammation by modulating TLR signalling.

Piccinini AM, Midwood KS - Mediators Inflamm. (2010)

DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913853&req=5

fig3: DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.
Mentions: The etiology of many inflammatory and autoimmune diseases is unclear; the initiating stimuli are often not well defined and the reasons why the mechanisms that ordinarily control the immune response fail are not known. However, it is clear that these diseases are characterized by an extremely destructive tissue environment. Accordingly, high levels of DAMPs occur locally and/or systemically in many of these conditions. For example, a wide range of endogenous TLR activators, including heat shock proteins, HMGB1, host DNA, fibrinogen, FNEDA, and tenascin-C, are observed in synovia of RA patients but not in synovia from normal joints or non-inflamed synovia from osteoarthritis (OA) patients [106–112]. High levels of HMGB1 and tenascin-C circulate in the serum of septic patients [113, 114], and high serum concentrations of DNA-containing immune complexes are associated with SLE [46], including nucleosome-HMGB1 complexes [90, 115]. In addition, elevated levels of low MW HA fragments are reported in the bronchial alveolar lavage fluid and serum of patients with inflammatory lung diseases [116–118]. In many cases levels of endogenous TLR activators are indicative of disease activity; elevated levels of extracellular HMGB1 localize specifically to active lesions of multiple sclerosis (MS) patients and correlate with active inflammation [119]. Furthermore, the S100 family of calcium binding proteins have long been reliable biomarkers of inflammation in a wide variety of diseases; for example, both MRP8 and MRP14 levels in the RA synovium and synovial fluid correlate with disease activity to a degree greater than levels of C-reactive protein (reviewed in [120]). Many endogenous TLR activators are also overexpressed in tumor cells. Figure 3 summarises some of the diseases with which endogenous TLR activators are associated.

Bottom Line: However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis.Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation.We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

View Article: PubMed Central - PubMed

Affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 65 Aspenlea Road, Hammersmith, London W6 8LH, UK.

ABSTRACT
Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Show MeSH
Related in: MedlinePlus