Review
The role of Toll-like receptors in chronic inflammation

https://doi.org/10.1016/j.biocel.2009.10.009Get rights and content

Abstract

The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been shown to be present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands during inflammation and consequently the activation of TLR signalling pathways may be one mechanism initiating and driving autoimmune diseases. An increasing body of circumstantial evidence implicates a role of TLR signalling in systemic lupus erythematosus (SLE), atherosclerosis, asthma, type 1 diabetes, multiple sclerosis, bowl inflammation and rheumatoid arthritis (RA). Although at present their involvement is not comprehensively defined. However, future therapies targeting individual TLRs or their signalling transducers may provide a more specific way of treating inflammatory diseases without global suppression of the immune system.

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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