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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

The “damage chain reaction.”  Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating TLRs. In turn, pro-inflammatory mediators are upregulated and trigger further tissue damage leading to increasing DAMPs levels. Thus a vicious cycle is sustained and may result in chronic inflammation and autoimmunity.
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Related In: Results  -  Collection


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fig4: The “damage chain reaction.” Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating TLRs. In turn, pro-inflammatory mediators are upregulated and trigger further tissue damage leading to increasing DAMPs levels. Thus a vicious cycle is sustained and may result in chronic inflammation and autoimmunity.

Mentions: It is apparent that low tissue levels of DAMPs are beneficial during tissue repair to induce a resolvable, physiological immune response. In contrast, high levels of DAMPs are generated during chronic inflammation. We propose a situation where a damage chain reaction occurs: increasing levels of pro-inflammatory DAMPs create more tissue damage which significantly amplifies the tissue levels of DAMPs which go on to create yet more tissue damage ad infinitum. These tissue levels of DAMPs become harmful and mediate a non-resolving perpetual inflammatory state (Figure 4). Thus targeting DAMP-mediated activation of TLRs may block this chronic inflammatory loop, although it will be important to assess whether total blockade of DAMP function will compromise tissue repair to any deleterious extent.


DAMPening inflammation by modulating TLR signalling.

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

The “damage chain reaction.”  Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating TLRs. In turn, pro-inflammatory mediators are upregulated and trigger further tissue damage leading to increasing DAMPs levels. Thus a vicious cycle is sustained and may result in chronic inflammation and autoimmunity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: The “damage chain reaction.” Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating TLRs. In turn, pro-inflammatory mediators are upregulated and trigger further tissue damage leading to increasing DAMPs levels. Thus a vicious cycle is sustained and may result in chronic inflammation and autoimmunity.
Mentions: It is apparent that low tissue levels of DAMPs are beneficial during tissue repair to induce a resolvable, physiological immune response. In contrast, high levels of DAMPs are generated during chronic inflammation. We propose a situation where a damage chain reaction occurs: increasing levels of pro-inflammatory DAMPs create more tissue damage which significantly amplifies the tissue levels of DAMPs which go on to create yet more tissue damage ad infinitum. These tissue levels of DAMPs become harmful and mediate a non-resolving perpetual inflammatory state (Figure 4). Thus targeting DAMP-mediated activation of TLRs may block this chronic inflammatory loop, although it will be important to assess whether total blockade of DAMP function will compromise tissue repair to any deleterious extent.

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