Toll-Like Receptor (TLR) Response Tolerance: A Key Physiological "Damage Limitation" Effect and an Important Potential Opportunity for Therapy

Applied Immunbiology and Transplantation Research Group, University of Newcastle, Newcastle-upon-Tyne, UK.
Current Medicinal Chemistry (Impact Factor: 3.85). 02/2006; 13(21):2487-502. DOI: 10.2174/092986706778201675
Source: PubMed


Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in pro-inflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or "re-booting" the immune system may be a useful therapeutic target in the post-septic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLR-ligands such as the gut and liver.

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    • "Endotoxin tolerance is a well-known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in pro-inflammatory cytokine release. With increasing understanding of the part played by TLR4 signalling in endotoxin release it has become clear that tolerance occurs to other TLR ligands in addition to endotoxin [36]. To test this as an explanation for the lower IL-6 and TNFa responses in preterm samples we used term non-laboured placentas from elective caesarean sections and treated them in vitro with the study TLR ligands, washed the tissue, and then re-exposed it to the TLR ligands. "
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    ABSTRACT: Toll-like receptor (TLR) activity within gestation-associated tissues might have a role in normal pregnancy progression as well as adverse obstetric outcomes such as preterm birth (PTB). The expression and activity of TLRs 1-9 in placentas collected following preterm vaginal delivery after infection-associated preterm labour (IA-PTL) at 25-36 weeks of gestation (preterm-svd, n = 10) were compared with those obtained after normal vaginal delivery at term (term-laboured; n = 17). Placental explants were cultured in the presence of agonists for TLR2, 3, 4, 5, 7, 8 and 9 and cytokine production after 24 h examined. Expression of TLR transcripts was determined using real time quantitative PCR. Reactivity to all agonists except CpG oligonucleotides was observed indicating that other than TLR9 all of the receptors studied yielded functional responses both term and preterm. Significantly less TNFα and IL-6, but not IL-10, were produced by preterm than term samples in response to all TLR agonists. Changes in TLR mRNA expression did not underlie functional differences in the preterm and term groups; nor does a pre-exposure/tolerance model mimic this finding. While glucocorticoids suppressed cytokine production in an in vitro model using term tissue the association between lower gestational age and decreased cytokine outputs suggests a temporally regulated response. Pro-inflammatory cytokine output in response to multiple TLR ligands was decreased in the preterm compared to the term placenta but gene expression for each TLR tended to be similar. Reduced cytokine production by the preterm placenta in response to stimulation of TLRs therefore must be regulated at the post-transcriptional level in a gestational age dependent manner. Copyright © 2015. Published by Elsevier Ltd.
    Placenta 07/2015; DOI:10.1016/j.placenta.2015.06.017 · 2.71 Impact Factor
    • "LPS is one of the most important virulence factors of gram-negative bacteria, and plays an essential role in triggering inflammation. Endotoxin tolerance induced by repeated LPS stimulations could lead to the reprogramming of the immune system with the aim to obtain a protective role against inflammatory tissue destruction [28]. The down-regulation of TNF-α and IL-1β, the main pro-inflammatory cytokines, and the preservation of IL-10, the main anti-inflammatory cytokine, seem to confirm this hypothesis. "
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    ABSTRACT: The age-related changes of immune system functions are complex phenomena incompletely understood. The acquired immune system shows a functional decline in ability to respond to new pathogens during aging, whereas serum levels of inflammatory cytokines are increased with age. The source of this age-related systemic chronic inflammation, named inflammaging, was mainly attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence can be an important additional contributor to chronic inflammation, since senescent cells acquire a phenotype named "senescence-associated secretory phenotype" (SASP), characterized by the enhanced secretion of many inflammation modulators. Pathogen-associated molecular pattern receptors, in particular Toll-like receptors (TLRs), are key molecules in the response of innate immunity cells to pathological stimuli. An intriguing and innovative hypothesis is that the dysfunction of TLRs signaling and the acquisition of SASP can be two interconnected phenomena. The TLR family, including receptors and co-effector molecules, do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signaling events, including inhibition of positive and activation of negative modulators of TLR signaling. MicroRNAs (miRNAs) are a newly discovered class of gene regulators acting as post-transcriptional repressors of a number of genes. The miRNA property to finely-tune gene expression makes them right for immune system regulation, which requires precise control for proper activity. We reviewed evidences suggesting that miRNAs can modulate TLR signaling mainly by three different mechanisms: 1) miRNAs can directly target components of the TLR signaling system, 2) miRNA expression can be directly regulated by TLRs pathway activation and 3) miRNAs can directly activate the RNA-sensing TLRs, like TLR-8, in humans. We also reviewed how TLR signaling is modulated by miRNAs during aging, and how an impaired miRNAs/TLR signaling interaction in immune system cells and related cells, i.e. endothelial cells and adipocytes, can contribute to inflammaging observed in normal aging. Interestingly, this impairment appears accelerated in presence of the majors age-related diseases, such as cardiovascular diseases, diabetes, neurodegenerative diseases and cancers.
    Immunity & Ageing 03/2013; 10(1):11. DOI:10.1186/1742-4933-10-11 · 3.54 Impact Factor
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    • "Over-activation of TLR4 with LPS leads to acute systemic disease known as endotoxic shock [27]. Endotoxin tolerance is a well described phenomenon involving TLR4 modulation, whereby cells exposed to LPS become less responsive to a continued or repeated exposure to this agonist [28], [29]. This may help to avoid the pathology associated with uncontrolled inflammation. "
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    ABSTRACT: Toll-like Receptors (TLR) are phylogenetically conserved transmembrane proteins responsible for detection of pathogens and activation of immune responses in diverse animal species. The stimulation of TLR by pathogen-derived molecules leads to the production of pro-inflammatory mediators including cytokines and nitric oxide. Although TLR-induced events are critical for immune induction, uncontrolled inflammation can be life threatening and regulation is a critical feature of TLR biology. We used an avian macrophage cell line (HD11) to determine the relationship between TLR agonist-induced activation of inflammatory responses and the transcriptional regulation of TLR. Exposure of macrophages to specific TLR agonists induced upregulation of cytokine and nitric oxide pathways that were inhibited by blocking various components of the TLR signalling pathways. TLR activation also led to changes in the levels of mRNA encoding the TLR responsible for recognising the inducing agonist (cognate regulation) and cross-regulation of other TLR (non-cognate regulation). Interestingly, in most cases, regulation of TLR mRNA was independent of NFκB activity but dependent on one or more of the MAPK pathway components. Moreover, the relative importance of ERK, JNK and p38 was dependent upon both the stimulating agonist and the target TLR. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR, immune induction and inflammation. Manipulation of these pathways during vaccination or management of acute inflammatory disease may lead to improved clinical outcome or enhanced vaccine efficacy.
    PLoS ONE 02/2013; 8(2):e51243. DOI:10.1371/journal.pone.0051243 · 3.23 Impact Factor
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