Endogenous ligands of Toll-like receptors

Tsan, Min‐Fu; Gao, Bo

doi:10.1189/jlb.0304127

Cited by 639 publications

(509 citation statements)

References 81 publications

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“…24 Other candidates include low molecular weight hyaluronan and fibrinogen from degraded extracellular matrix, as well as heat-shock proteins from necrotic cells. 25 A similar role of TLR4 was revealed in a murine myocardial ischemia reperfusion model in which TLR4 KO suffered smaller infarctions than TLR2 KO mice. 14,26 In contrast, the parenchyma TLR2 was an important initiator of inflammatory responses leading to renal dysfunction and kidney IRI.…”

Section: Discussionmentioning

confidence: 67%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4°C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4 ϩ T cell infiltration, interferon (IFN)-␥-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-2, and IFN-␥, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses. Liver Transpl 13:1435-1443, 2007. © 2007 AASLD. Received February 7, 2007 accepted May 19, 2007.The ischemia and reperfusion injury (IRI), an antigenindependent event, is an unavoidable consequence of liver transplantation. The IRI causes up to 10% of early organ failure, and can lead to a higher incidence of both acute and chronic rejection. Indeed, IRI is more frequently observed with the use of marginal donors or following prolonged cold ischemia times. 1-3 Moreover, IRI contributes to the shortage of livers available for transplantation because of the higher susceptibility of marginal organs to the ischemic insult. Thus, minimizing the impact of IRI could significantly increase the number of patients successfully undergoing liver transplantation. The mechanisms of IRI include activation of Kupffer cells with production of reactive oxygen species, upregulation of the inducible nitric oxide synthase, release of proinflammatory cytokines, increased expres-

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Section: Discussionmentioning

confidence: 67%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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“…In the case of extracellular PAMPs, one of the major sensors is TLRs 74,75 As PAMPs and DAMPs both have adjuvant and inflammatory properties one possibility is that they actually work through the same receptors 74 . A potential role for TLRs has been explored so far primarily in inflammatory responses stimulated by dead cells and selected DAMPs (Table I).…”

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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“…Ability of heat shock proteins to elicit a wide range of immunological effects has instigated scientific community in finding cell surface receptors for these molecules. It has been shown that the heat shock proteins mediate these immunological effects by binding with specific receptors like CD14, Toll like receptor 2 and 4 and CD91 [24,25].…”

Section: Heat Shock Proteins In Intercellular Signaling and Antigen Pmentioning

confidence: 99%

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

Kaul

Thippeswamy

2011

Indian J Microbiol

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Heat shock proteins are ubiquitously expressed intracellular proteins and act as molecular chaperones in processes like protein folding and protein trafficking between different intracellular compartments. They are induced during stress conditions like oxidative stress, nutritional deficiencies and radiation. They are released into extracellular compartment during necrosis. However, recent research findings highlights that, they are not solely present in cytoplasm, but also released into extracellular compartment during normal conditions and even in the absence of necrosis. When present in extracellular compartment, they have been shown to perform various functions like antigen presentation, intercellular signaling and induction of pro-inflammatory cytokines. Heat shock proteins represents as dominant microbial antigens during infection. The phylogenetic similarity between prokaryotic and eukaryotic heat shock proteins has led to proposition that, microbial heat shock proteins can induce self reactivity to host heat shock proteins and result in autoimmune diseases. The self-reactivity of heat shock proteins protects host against disease by controlling induction and release of pro-inflammatory cytokines. However, antibodies to self heat shock proteins haven been implicated in pathogenesis of autoimmune diseases like arthritis and atherosclerosis. Some heat shock proteins are potent inducers of innate and adaptive immunity. They activate dendritic cells and natural killer cells through toll-like receptors, CD14 and CD91. They play an important role in MHC-antigen processing and presentation. These immune effector functions of heat shock proteins are being exploited them as therapeutic agents as well as therapeutic targets for various infectious diseases and cancers.

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Endogenous ligands of Toll-like receptors

Cited by 639 publications

References 81 publications

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

How dying cells alert the immune system to danger

Role of Heat Shock Proteins in Diseases and Their Therapeutic Potential

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