Differential effects of CpG‐DNA in Toll‐like receptor‐2/‐4/‐9 tolerance and cross‐tolerance

Dalpke, Alexander H.; Lehner, Martin D.; Hartung, Thomas; Heeg, Klaus

doi:10.1111/j.1365-2567.2005.02211.x

Cited by 95 publications

(100 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because flagellin is linked to a wide range of diseases and might induce significant liver damage based on our observations 25 and those of other studies, 23,27 flagellin might be an essential determinant of liver injury. However, flagellin can also activate the inflammasome NLRC4 pathway in addition to TLR5 signaling.…”

Section: Introductionmentioning

confidence: 90%

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

View full text Add to dashboard Cite

Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for vaccines, and it might function as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated flagellin in the occurrence of some inflammatory diseases, such as acute lung inflammation, cardiovascular collapse and inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-TLR5 signaling activation plays a role in the pathophysiology of liver or whether some other flagellin activity also contributes to liver injury either via bacterial infections or during clinical applications. Recombinant flagellin proteins with or without TLR5-stimulating activity were used to evaluate the role of flagellin-TLR5 signaling in liver injury in wild-type and TLR5 KO mice. Gross lesions and large areas of hepatocellular necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 mg flagellin (FliC) in a dose-and time-dependent manner in wild-type mice, but not in TLR5 KO mice. Deletion of the N-terminal or TLR5 binding domain of flagellin inhibited flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that flagellin is an essential determinant of liver injury and demonstrated that the over-activation of TLR5 signaling by high-dose flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of flagellin-induced liver injury.

show abstract

Section: Introductionmentioning

confidence: 90%

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These include a possible role for TAM-receptor-mediated inhibition of endotoxin tolerance and immune suppression -phenomena in which hypo-responsiveness to TLR engagement is induced by prior TLR activation 83,84 . In macrophages, components of the TAM pathway that are upregulated during inflammation must turn over with a half-life that allows responding cells to return to their baseline levels.…”

Section: Prospects and Implicationsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

show abstract

“…Cross talk may be induced after simultaneous triggering of different TLRs. 21 Particularly, TLR3-and TLR9-induced type I IFN may modulate mDC activation. 22 It is also likely that mDCs and pDCs positioned in the atherosclerotic plaque are aware of each other and cross-regulate each other's function.…”

Section: Clinical Perspective P 2052mentioning

confidence: 99%

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

et al. 2007

View full text Add to dashboard Cite

show abstract

Differential effects of CpG‐DNA in Toll‐like receptor‐2/‐4/‐9 tolerance and cross‐tolerance

Cited by 95 publications

References 51 publications

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Immunobiology of the TAM receptors

Synergistic Proinflammatory Effects of the Antiviral Cytokine Interferon-α and Toll-Like Receptor 4 Ligands in the Atherosclerotic Plaque

Contact Info

Product

Resources

About