The strength and pervasive nature of Toll-like receptor (TLR) signalling necessitates a powerful and comprehensive negative regulatory mechanism to prevent autoimmune damage. This review discusses our current understanding of the negative regulators of TLR responses.
There are at least five layers of negative regulation of TLR signalling. These range from extracellular decoy receptors to intracellular inhibitors, membrane-bound suppressors, degradation of TLRs, and TLR-induced apoptosis.
Soluble decoy TLRs are potentially powerful competitors for TLR agonists, reminiscent of soluble chemokines and cytokine receptors. So far, only soluble TLR4 and TLR2 have been identified, and their role might be as an important first-line negative regulatory mechanism.
Intracellular negative regulators so far identified include MyD88s, IRAKM, SOCS1, NOD2, phosphatidylinositol 3-kinase, TOLLIP and A20. This group is perhaps the best studied of all the regulators. They function at various stages of the TLR signalling cascade but concentrate principally on the MyD88-dependent pathway.
Transmembrane protein regulators include ST2, SIGIRR, TRAILR and RP105. These proteins inhibit TLR functions either by sequestration of adaptor proteins (ST2) and transcription factors (TRAILR), or by interfering with the binding of TLR agonists to their respective TLRs (SIGIRR and RP105).
Reduction of TLR expression could be by ubiquitylation (TRIAD3A), promoting proteolytic degradation of TLRs, or through inhibition of the transcription or stability of TLR-encoding mRNAs (interleukin-10, transforming-growth factor-β and lipopolysaccharide).
The last line of negative regulation is self-destruction. Excessive TLR activation could lead to caspase-dependent (through the death domain of MyD88) and caspase-independent apoptosis.
The existence of multiple and apparently non-redundant negative regulators of TLRs indicate that either the regulators function in a cascade manner or that each regulator is necessary but insufficient to control a particular TLR signalling pathway. The genetic polymorphism of the regulators and what regulates the negative regulator remains to be determined. The biological functions of some of the negative regulators in vivo also remain to be determined.
Toll-like receptors (TLRs) are involved in host defence against invading pathogens, functioning as primary sensors of microbial products and activating signalling pathways that induce the expression of immune and pro-inflammatory genes. However, TLRs have also been implicated in several immune-mediated and inflammatory diseases. As the immune system needs to constantly strike a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signalling must be tightly regulated. Here, we discuss the various negative regulatory mechanisms that have evolved to attenuate TLR signalling to maintain this immunological balance.
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We thank The Wellcome Trust, The Medical Research Council, UK, The Science Foundation Ireland and the European Commission for financial support.
The authors declare no competing financial interests.
- PATHOGEN-ASSOCIATED MOLECULAR PATTERN
A molecular pattern that is found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind TLRs.
- ORPHAN RECEPTOR
A receptor without a known ligand.
- TIR DOMAIN
An amino-acid sequence of the cytoplasmic region that is highly conserved among TLRs and IL-1 receptor superfamily.
- CpG DNA
DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides, which have been found to induce innate immune responses through interaction with TLR9.
- LPS TOLERANCE
A transient state of hypo-responsiveness to subsequent stimulation with lipopolysaccharide (LPS), which is induced by the administration of TLR ligands in vivo and in vitro.
- ENDOTOXIN SHOCK
A clinical condition that is induced by hyper-reactivity of the innate immune system to bacterial LPS. It is mediated by the pro-inflammatory cytokines interleukin-1 (IL-1) and tumour-necrosis factor (TNF), which are produced in high amounts owing to sustained stimulation of TLR4 by LPS.
- CROHN'S DISEASE
A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is believed to result from an abnormal T-cell-mediated immune response to commensal bacteria.
- IL-1 RECEPTOR ACCESSORY PROTEIN
A protein that forms a heterodimer with the type I IL-1 receptor. IL-1 receptor accessory protein does not bind IL-1 directly on its own but is essential for downstream IL-1 receptor complex signalling.
The attachment of the small protein ubiquitin to lysine residues present in other proteins. This tags these proteins for rapid cellular degradation.
Slow rate of heart beat contraction, resulting in slow pulse rate. In febrile states, for each degree rise in body temperature, the expected increase in pulse rate is 10 beats per minute. When the latter does not occur, the term 'relative bradycardia' is used.
- SMALL INTERFERING RNA
Short (∼21-base pairs) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.
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Liew, F., Xu, D., Brint, E. et al. Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol 5, 446–458 (2005). https://doi.org/10.1038/nri1630
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