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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

Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular compartments. (*)HMGB1 may require MD-2 and CD14 for TLR4 activation (see [96]).
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Related In: Results  -  Collection


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fig2: Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular compartments. (*)HMGB1 may require MD-2 and CD14 for TLR4 activation (see [96]).

Mentions: There is also evidence that DAMPs require different co-receptors and accessory molecules to PAMPs. Reviewing the proposed modes of endogenous ligand recognition leads to a rational classification of endogenous molecules based on the receptor, co-receptor(s), and accessory molecule(s) requirement for recognition by TLR(s) and subsequent cellular activation that is summarized in Figure 2. A first group of DAMPs requires both CD14 and MD-2. This includes both TLR2 and 4 agonists, such as HSP60, HSP70, and biglycan, as well as TLR4 activators such as oxidized LDL and S100 proteins [15, 23, 69, 76, 77]. A second group of DAMPs requires only CD14 as an accessory molecule and these are surfactant protein A and D and lactoferrin [78–80]. A third group comprises DAMPs that have been shown to involve only MD-2 in their recognition by TLRs. Among these, Gp96 and HMGB1 activate TLR2 and 4, whereas fibronectin EDA (FNEDA) and saturated fatty acids activate TLR4 [17, 20, 22, 81–86]. A fourth group includes DAMPs that use co-receptors or accessory molecules different from CD14 and MD-2. Biglycan was recently shown to induce the NLRP3/ASC inflammasome through activation of TLR2/4 and purinergic P2X4/P2X7 receptors [87]. Versican-induced responses require TLR2, TLR6, and CD14 [25]. HA dependent TLR4 activation involves CD44 in addition to MD-2 [88]. Autoantibodies against dsDNA and nucleosomes from SLE patients induce DC activation through TLR2 if bound to HMGB1 [89, 90]. Similarly, HMGB1 mediates the activation of plasmacytoid DCs and B cells through TLR9 by DNA-containing immune complexes through a mechanism involving the immunoglobulin superfamily member RAGE [46]. IgG2a-chromatin immune complexes require the synergistic engagement of IgM and TLR9 to activate B cells [31]. TLR7, 8, and TLR9 expressed by pDCs respond to self-RNA and -DNA respectively when coupled with the endogenous antimicrobial peptide LL37 [91, 92]. Furthermore, CD32 delivers DNA-containing immune complexes found in serum from SLE patients to intracellular lysosomes containing TLR9, leading to DC activation [89, 90]. Finally, B cells are activated by DNA- or RNA-associated autoantigens by combined B cell antigen receptor (BCR)/TLR9 or TLR7 engagement [93, 94]. This is a provisional list of endogenous activators and their accessory molecules that will certainly expand as we learn more about DAMP-TLR interactions. Collectively, these data indicate that several co-receptors and accessory molecules required for ligand recognition by TLRs are employed by both DAMPs and PAMPs. Further detailed investigation of how DAMPs are recognised by the cell is required to elucidate the precise structural organization of these receptor complexes. A signalling competent conformation of the receptor is required for TLRs to function; however it is not known whether the conformation induced by DAMPs is similar or distinct to that produced by microbial structures where sequential changes in receptor conformation occur upon ligand binding (reviewed in [95]).


DAMPening inflammation by modulating TLR signalling.

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

Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular compartments. (*)HMGB1 may require MD-2 and CD14 for TLR4 activation (see [96]).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular compartments. (*)HMGB1 may require MD-2 and CD14 for TLR4 activation (see [96]).
Mentions: There is also evidence that DAMPs require different co-receptors and accessory molecules to PAMPs. Reviewing the proposed modes of endogenous ligand recognition leads to a rational classification of endogenous molecules based on the receptor, co-receptor(s), and accessory molecule(s) requirement for recognition by TLR(s) and subsequent cellular activation that is summarized in Figure 2. A first group of DAMPs requires both CD14 and MD-2. This includes both TLR2 and 4 agonists, such as HSP60, HSP70, and biglycan, as well as TLR4 activators such as oxidized LDL and S100 proteins [15, 23, 69, 76, 77]. A second group of DAMPs requires only CD14 as an accessory molecule and these are surfactant protein A and D and lactoferrin [78–80]. A third group comprises DAMPs that have been shown to involve only MD-2 in their recognition by TLRs. Among these, Gp96 and HMGB1 activate TLR2 and 4, whereas fibronectin EDA (FNEDA) and saturated fatty acids activate TLR4 [17, 20, 22, 81–86]. A fourth group includes DAMPs that use co-receptors or accessory molecules different from CD14 and MD-2. Biglycan was recently shown to induce the NLRP3/ASC inflammasome through activation of TLR2/4 and purinergic P2X4/P2X7 receptors [87]. Versican-induced responses require TLR2, TLR6, and CD14 [25]. HA dependent TLR4 activation involves CD44 in addition to MD-2 [88]. Autoantibodies against dsDNA and nucleosomes from SLE patients induce DC activation through TLR2 if bound to HMGB1 [89, 90]. Similarly, HMGB1 mediates the activation of plasmacytoid DCs and B cells through TLR9 by DNA-containing immune complexes through a mechanism involving the immunoglobulin superfamily member RAGE [46]. IgG2a-chromatin immune complexes require the synergistic engagement of IgM and TLR9 to activate B cells [31]. TLR7, 8, and TLR9 expressed by pDCs respond to self-RNA and -DNA respectively when coupled with the endogenous antimicrobial peptide LL37 [91, 92]. Furthermore, CD32 delivers DNA-containing immune complexes found in serum from SLE patients to intracellular lysosomes containing TLR9, leading to DC activation [89, 90]. Finally, B cells are activated by DNA- or RNA-associated autoantigens by combined B cell antigen receptor (BCR)/TLR9 or TLR7 engagement [93, 94]. This is a provisional list of endogenous activators and their accessory molecules that will certainly expand as we learn more about DAMP-TLR interactions. Collectively, these data indicate that several co-receptors and accessory molecules required for ligand recognition by TLRs are employed by both DAMPs and PAMPs. Further detailed investigation of how DAMPs are recognised by the cell is required to elucidate the precise structural organization of these receptor complexes. A signalling competent conformation of the receptor is required for TLRs to function; however it is not known whether the conformation induced by DAMPs is similar or distinct to that produced by microbial structures where sequential changes in receptor conformation occur upon ligand binding (reviewed in [95]).

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