The International Journal of Biochemistry & Cell Biology
ReviewThe role of Toll-like receptors in chronic inflammation
Section snippets
Signalling pathways of Toll-like receptors
TLRs are expressed by a great variety of cell types including professional immune cells, e.g. dendritic cells (DCs) as well as non-professional immune cells, e.g. synovial fibroblast-like cells and epithelial cells (Radstake et al., 2004, Seibl et al., 2003, Iwahashi et al., 2004). It is becoming clear now that TLRs, rather than having one single mode of action, perform distinct functions depending on the cell type and tissue they are expressed in (Jiang et al., 2005, Lee and Kim, 2007,
Regulation of TLR signalling
Given the potency of the inflammatory response induced by TLRs, these signalling pathways must be tightly regulated to reduce the risk of excessive cell damage (reviewed in Liew et al., 2005). Regulatory mechanisms, inhibiting TLR signalling, have been described at all levels of signal transduction. In the case of TLR2 and TLR4 extracellular decoy receptors have been shown to function as antagonists, inhibiting the binding of the ligand to the receptor (Iwami et al., 2000, LeBouder et al., 2003
TLRs are also stimulated by endogenous ligands
The main function of TLRs is considered to be the recognition and response to microbial pathogens. More recently, however, they have also been reported to recognise endogenous ligands, so called “danger signals”, which are released during tissue damage, infections and cell necrosis. A precedence for the recognition of endogenous ligands exists in the evolutionary conserved Toll pathway in D. melanogaster which has originally been described to be involved in fly development, suggesting the
TLRs and their role in inflammatory diseases, injury and cancer
TLRs are emerging as major factors in many disease conditions. Several studies have emphasized a role for TLRs in the promotion of systemic lupus erythematosus (SLE), asthma, Crohn's disease, multiple sclerosis, type 1 diabetes, and RA (Table 1).
Conclusions
The role of TLRs as a first line of defence against microbial infection is well established (Akira and Takeda, 2004). The potent inflammatory response induced by TLRs is protective in most cases as the pathogens are destroyed before they can harm the host. However, if inflammation persists it can result in autoimmune/inflammatory diseases. Therefore, TLR signalling needs to be tightly regulated (Liew et al., 2005). This is achieved through negative feedback loops that are present in most cells,
Acknowledgments
The authors thank Dr. Rachel Simmonds and Dr. Jeremy Turner for critical reading of the manuscript.
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