Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 4

Smiley, Stephen T.; King, Jennifer; Hancock, Wayne W.

doi:10.4049/jimmunol.167.5.2887

Cited by 874 publications

(626 citation statements)

References 64 publications

(57 reference statements)

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“…These include cellular molecules that directly activate the complement cascade 66,67 or cleave extracellular matrix molecules such as collagen 68 69, fibrillar protein 70 , hyaluronic acid 71 and heparan sulfate 72 into proinflammatory fragments. Cellular molecules may also trigger the clotting, fibrinolytic and kinin cascades which generate other proinflammatory mediators 73 .…”

Section: Extracellular Damps and Other Mediatorsmentioning

confidence: 99%

“…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%

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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: Extracellular Damps and Other Mediatorsmentioning

confidence: 99%

Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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“…A number of putative endogenous TLR ligands have already been studied in vitro, including heat shock protein 60 (Hsp60), 78 fibronectin, 79 and the extra domain A of fibrinogen. 80 Recent data have also demonstrated that low-molecular weight soluble hyaluronan (sHA) fragments derived from the extracellular matrix at sites of inflammation are able to induce DC maturation in vitro as well as in vivo through TLR4. 81 Finally, identification of all relevant TLR ligands, combined with a comprehensive understanding of the different intracellular signaling pathways and repertoire of downstream targets activated by individual TLRs and their various combinations will significantly advance our understanding of host-pathogen interactions.…”

Section: Future Directionsmentioning

confidence: 99%

Toll-like receptors and their role in experimental models of microbial infection

2003

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Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

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“…Bacterial PG was identified in RA synovial tissue by a monoclonal antibody, particularly in macrophages and antigen-presenting cells (20,21). Additionally, endogenous mammalian TLR agonists, including fibrinogen, extra domain A (ED-A) of fibronectin, Hsp60 and Hsp70, low molecular weight fragments of hyaluronic acid, and high mobility group box chromosomal protein 1 (HMGB-1), a highly conserved nuclear protein that stabilizes nucleosome formation, are expressed in the RA joint, and each has been shown to activate NF-B through TLR-4 and/or TLR-2 (22)(23)(24)(25)(26)(27)(28)(29).…”

mentioning

confidence: 99%