Advances in Toll-like receptor biology: Modes of activation by diverse stimuli

Abstract

As we learn more about the biology of the Toll-like receptors (TLRs), a wide range of molecules that can activate this fascinating family of pattern recognition receptors emerges. In addition to conserved pathogenic components, endogenous danger signals created upon tissue damage are also sensed by TLRs. Detection of these types of stimuli results in TLR mediated inflammation that is vital to fight pathogenic invasion and drive tissue repair. Aberrant activation of TLRs by pathogenic and endogenous ligands has also been linked with the pathogenesis of an increasing number of infectious and autoimmune diseases, respectively. Most recently, allergen activation of TLRs has also been described, creating a third broad class of TLR stimulus that has helped to shed light on the pathogenesis of allergic disease. To date, microbial activation of TLRs remains best characterized. Each member of the TLR family senses a specific subset of pathogenic ligands, pathogen associated molecular patterns (PAMPS), and a wealth of structural and biochemical data continues to reveal the molecular mechanisms of TLR activation by PAMPs, and to demonstrate how receptor specificity is achieved. In contrast, the mechanisms by which endogenous molecules and allergens activate TLRs remain much more mysterious. Here, we provide an overview of our current knowledge of how very diverse stimuli activate the same TLRs and the structural basis of these modes of immunity.

• Allergens
• endogenous stimuli
• extracellular matrix
• glycoproteins
• nucleic acids
• pathogen recognition
• small leucine rich proteoglycans
• structure
• Toll-like receptors

Acknowledgements

We would like to apologize to any colleagues whose work we failed to cite due to space constraints. K.S.M. thanks Lorena Zuliani-Alvarez, and N.J.G. thanks Martyn Symmons, for assistance with illustrations.

Declaration of interest

This work was supported by: a UK Medical Research Council programme grant (G1000133) to N.J.G. and C.E.B., a Welcome Investigator award to N.J.G. (WT100321/z/12/Z), a Medical Research Council grant (G1001715) to S.S., and funding from the Kennedy Trust for Rheumatology Research and a Senior Research Fellowship from Arthritis Research UK (20003) to K.S.M. Original research on DAMP biology in the laboratory of L.S. was supported by the German Research Council (SFB 815, project A5, SFB 1039, project B2, Excellence Cluster ECCPS, and LOEWE program Ub-Net. S.H. received funding for this review from the European Union Commission’s Seventh Framework programme under grant agreement No. 602904 (FIBROTARGETS) and No. 261409 (MEDIA) and No. 602156 (HECATOS). It was supported by collaborative research grant of the NHS and NWO, CVON 2011-11 ARENA. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.