Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

Liu‐Bryan, Ru; Scott, Peter C.; Sydlaske, Anya D.; Rose, David M.; Terkeltaub, Robert

doi:10.1002/art.21238

Cited by 341 publications

(271 citation statements)

References 51 publications

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“…These include HMGB1 76 31, uric acid 77 , some HSPs 78 79, some defensins [G] 80 , hyaluronic acid 81 , heparan sulfate 82 , and some fragments of extracellular matrix proteins 70 . Whereas this data may well be correct, caution is warranted because TLRs can be stimulated by microbial contaminants that are easily introduced during the purification of molecules.…”

Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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“…There are data implicating both TLR-2 and -4 in mediating some cellular actions of UA. 11 Moreover, a recent report suggested that TLR-2 activation triggers exocytosis of WPB. 12 Consequently, we attempted to dissect relations between UA, TLR, and exocytosis of WPB in vivo using TLR-2 and TLR-4 knockout mice.…”

Section: Tlr-4 Mediates the Action Of Uric Acid On Wpbmentioning

confidence: 99%

Ischemia-Induced Exocytosis of Weibel-Palade Bodies Mobilizes Stem Cells

Kuo

Patschan

et al. 2008

Journal of the American Society of Nephrology

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Recruitment of various stem and progenitor cells is crucial for the regeneration of an injured organ. Levels of uric acid, one of the prototypical "alarm signals," surge after ischemia-reperfusion injury. Exogenous uric acid rapidly mobilizes endothelial progenitor cells and hematopoietic stem cells and protects the kidney from ischemia. The relatively fast responses to uric acid suggest that preformed second messengers may be released from a storage pool. Here, it is reported that monosodium urate (MSU) results in exocytosis of Weibel-Palade bodies in vitro and in vivo, leading to the release of IL-8, von Willebrand factor, and angiopoietin 2 in the culture medium or circulation. Confocal and immunoelectron microscopy confirmed depletion of von Willebrand factor in MSU-treated aortic endothelial cells. Angiopoietin 2 alone induced exocytosis of Weibel-Palade bodies, mobilized hematopoietic stem cells and depleted splenic endothelial progenitor cells, partially reproducing the actions of MSU. In addition, pretreatment with angiopoietin 2 protected the kidneys from an ischemic insult, suggesting that the previously reported renoprotection conferred by MSU likely results from exocytosis of Weibel-Palade bodies. Furthermore, experiments with toll-like receptor 4 (TLR-4)-and TLR-2-deficient mice demonstrated that uric acid-induced exocytosis of Weibel-Palade bodies is mediated by TLR-4 and that uric acid-induced release of IL-8 requires both TLR-2 and TLR-4. In summary, these results suggest that exocytosis of Weibel-Palade bodies links postischemic repair with inflammation and mobilization of stem cells.

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“…In a series of recent studies, we implicated innate immune inflammatory responses to the naked crystal surface in the pathogenesis of acute gout (9)(10)(11). The process, set into motion partly via C5 cleavage catalyzed by the MSU crystal surface (12), involves terminal complement membrane attack complex formation that drives activation of the endothelium and generation of the major MSU crystal-induced neutrophil chemotaxin CXCL8 (interleukin-8 [IL-8]) (13,14) in vivo (9).…”

Section: Innate Immune Recognition Of the Naked Msu Crystal Surface Amentioning

confidence: 99%

“…The process, set into motion partly via C5 cleavage catalyzed by the MSU crystal surface (12), involves terminal complement membrane attack complex formation that drives activation of the endothelium and generation of the major MSU crystal-induced neutrophil chemotaxin CXCL8 (interleukin-8 [IL-8]) (13,14) in vivo (9). We determined recognition of naked MSU crystals by TLR-2 in chondrocytes, and by TLR-2 and TLR-4 in macrophage lineage cells, to be critical for the respective capacities of inert MSU crystals to turn on resident mesenchymal lineage cells in the joint and induce macrophage lineage cell expression of proinflammatory cytokines (10,11). Particularly pivotal to MSU crystalinduced cell activation in vitro and acute MSU crystalinduced inflammation in vivo was myeloid differentiation factor 88 (MyD88) signaling, which transduces TLR-2 responses, some TLR-4 responses, as well as IL-1-induced cell activation (10,11).…”

Section: Innate Immune Recognition Of the Naked Msu Crystal Surface Amentioning

confidence: 99%

“…We determined recognition of naked MSU crystals by TLR-2 in chondrocytes, and by TLR-2 and TLR-4 in macrophage lineage cells, to be critical for the respective capacities of inert MSU crystals to turn on resident mesenchymal lineage cells in the joint and induce macrophage lineage cell expression of proinflammatory cytokines (10,11). Particularly pivotal to MSU crystalinduced cell activation in vitro and acute MSU crystalinduced inflammation in vivo was myeloid differentiation factor 88 (MyD88) signaling, which transduces TLR-2 responses, some TLR-4 responses, as well as IL-1-induced cell activation (10,11).…”

Section: Innate Immune Recognition Of the Naked Msu Crystal Surface Amentioning

confidence: 99%

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