TLRs: Professor Mechnikov, sit on your hat

doi:10.1016/j.it.2004.10.005

Trends in Immunology

Volume 25, Issue 12, December 2004, Pages 687-693

https://doi.org/10.1016/j.it.2004.10.005 Get rights and content

Toll-like receptors (TLRs) are sensors of foreign microbial products, which initiate host defense responses in all multicellular organisms examined to date. They are the target for most adjuvants, are essential for the establishment of memory in T and B cells and provoke inflammation. They program dendritic cells in their interaction with Th1 cells and their signalling pathways enable a tailoring of host defense responses to the provoking microbe previously unsuspected in the innate arm of immunity. Their discovery and characterisation fills a void in immunology and is the culmination of an effort that began with one of immunology's founding fathers, Elie Mechnikov. Targeting TLRs therapeutically now has the potential to impact on how we treat infectious and inflammatory diseases.

Section snippets

From endogenous pyrogen to TLRs

How did the TLR field begin? Figure 1 describes the key discoveries involved. In molecular terms, the first protein we can identify as being important in the process that led to the discovery of the TLRs is the type I interleukin-1 (IL-1) receptor. Another triumph in immunology over the past 25 years is the description of cytokines, proteins that mediate the maturation, differentiation and activation of immune and inflammatory cells. IL-1 was among the first of the cytokines to be described and

Can we believe the hype?

Can it really be true that TLRs kick off all immunity? Four examples will suffice here to make the case.

Where to now? Lampreys, negative signals and drugs

Three aspects relevant to TLRs are currently receiving much attention. The first of these concerns the evolution of host defense systems, which largely relies on comparative immunology. One particular recent study stands out in this regard. As stated earlier, TLRs possess two domains, an extracellular LRR domain and an intracellular TIR domain. IL-1RI and related receptors have Ig domains extracellularly. This is of interest because the Ig domain forms the basis of diversity in antibodies and

Concluding remarks

To conclude, when naming TLRs as one of key discoveries in immunology in the past 25 years, we might return to one of immunology's founding fathers, Elie Mechnikov, who won the Nobel prize in 1908 for his discovery of cellular immunity. When Mechikov became excited by a scientific discovery he was wont to sit on his hat. If he were alive today, he would be permanently sitting on his hat, given all of the discoveries in the field of TLRs. TLRs finally provide the most important molecular basis

Acknowledgements

I wish to thank Science Foundation Ireland, the Health Research Board and Enterprise Ireland for financial support, and all of the people who have spent time in my laboratory for making research and discussions on IL-1, NF-κB and latterly TLRs such a blast.

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MyD88-dependent and -independent signalling via TLR3 and TLR4 are differentially modulated by Δ<sup>9</sup>-tetrahydrocannabinol and cannabidiol in human macrophages
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TLRs can intricately distinguish between bacterial and viral molecules to initiate innate immune responses via nuclear factor (NF)-κB and interferon (IFN) regulatory factor (IRF) transcription factors, to orchestrate the cellular production of cytokines, chemokines and type I IFNs. TLRs are localized in cellular membranes (TLR1, TLR2, TLR4, TLR5, TLR6, TLR10) or endosomal compartments (TLR3, TLR7, TLR8, TLR9) (O'Neill, 2004b), and the specificity in cellular response is dependent on the TLR adaptor proteins that are engaged by the receptor (O'Neill, 2004a). All TLRs signal via the adaptor myeloid differentiation factor 88 (MyD88), while TLR3 is an exception, signalling via Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor-inducing IFN-β (TRIF) adaptor to induce MyD88-independent signalling.
Toll-like receptors (TLRs) are sensors of pathogen-associated molecules that trigger inflammatory signalling in innate immune cells including macrophages. All TLRs, with the exception of TLR3, promote intracellular signalling via recruitment of the myeloid differentiation factor 88 (MyD88) adaptor, while TLR3 signals via Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor-inducing interferon (IFN)-β (TRIF) adaptor to induce MyD88-independent signalling. Furthermore, TLR4 can activate both MyD88-dependent and –independent signalling (via TRIF). The study aim was to decipher the impact of the highly purified plant-derived (phyto) cannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), when delivered in isolation and in combination (1:1), on MyD88-dependent and -independent signalling in macrophages. We employed the use of the viral dsRNA mimetic poly(I:C) and endotoxin lipopolysaccharide (LPS), to induce viral TLR3 and bacterial TLR4 signalling in human Tamm-Horsfall protein-1 (THP-1)-derived macrophages, respectively. TLR3/TLR4 stimulation promoted the activation of interferon (IFN) regulatory factor 3 (IRF3) and TLR4 promoted the activation of nuclear factor (NF)-κB signalling, with downstream production of the type I IFN-β, the chemokines CXCL10 and CXCL8, and cytokine TNF-α. THC and CBD (both at 10 μM) attenuated TLR3/4-induced IRF3 activation and induction of CXCL10/IFN-β, while both phytocannabinoids failed to impact TLR4-induced IκB-α degradation and TNF-α/CXCL8 expression. The role of CB₁, CB₂ and PPARγ receptors in mediating the effect of THC and CBD on MyD88-independent signalling was investigated. TLRs are attractive therapeutic targets given their role in inflammation and initiation of adaptive immunity, and data herein indicate that both CBD and THC preferentially modulate TLR3 and TLR4 signalling via MyD88-independent mechanisms in macrophages. This offers mechanistic insight into the role of phytocannabinoids in modulating cellular inflammation.
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De novo transcriptome analysis of immune response on cobia (Rachycentron canadum) infected with Photobacterium damselae subsp. piscicida revealed inhibition of complement components and involvement of MyD88-independent pathway
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Cobia, Rachycentron canadum, one of the most important aquatic species in Taiwan, has suffered heavy losses from Photobacterium damselae subsp. piscicida, which is the causal agent of photobacteriosis. In this study, the transcriptomic profiles of livers and spleens from Pdp-infected and non-infected cobia were obtained for the first time by Illumina-based paired-end sequencing method with a focus on immune-related genes. In total, 164,882 high quality unigenes were obtained in four libraries. Following Pdp infection, 7302 differentially expressed unigenes from liver and 8600 differentially expressed unigenes from spleen were identified. Twenty-seven of the differently expressed genes were further validated by RT-qPCR (average correlation coefficient 0.839, p-value <0.01). Results indicated a negative regulation of complement components and increased expression of genes involved in MyD88-independent pathway. Moreover, a remarkable finding was the increased expression of IL-10, implying an inadequacy of immune responses. This study not only characterized several putative immune pathways, but also provided a better understanding of the molecular responses to photobacteriosis in cobia.
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The major sex hormones that have been studied in immunity are estrogens, testosterone, progesterone, and vitamin D. Sex hormones bind to hormone receptors on the surface of immune cells or more classically, within the cytoplasm of the cell. Most immune cells express multiple sex hormone receptors that are involved in driving immune responses in sex-specific directions following antigen stimulation. Sex hormone regulation of innate antigen-presenting cells like dendritic cells, mast cells, and monocyte/macrophages is the key step in determining the type of adaptive immune response. Sex hormone receptors on adaptive T and B cells further distinguish sex differences in inflammation that characterize the immune response to infections and the development of chronic inflammatory diseases like autoimmune diseases. However, data are contradictory and further research is needed to better understand how sex hormone receptors regulate inflammation. This chapter describes current knowledge on how sex hormones alter the function of innate immune cells like dendritic cells, mast cells, macrophages, and adaptive immune cells like T cells, T regulatory cells, and B cells. Detailed descriptions of the downstream signaling pathways of major sex hormone receptors are also provided.
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Citation Excerpt :
TLRs, through recognition of structural motifs associated with pathogenic microorganisms such as viral DNA and bacterial cell wall components or endogenous factors associated with cellular damage (danger-associated molecular patterns; DAMPs), orchestrate a rapid inflammatory response, recruitment of immunocompetant cells and elimination of pathogens (Knapp, 2010; Moynagh, 2005; Netea et al., 2006). Thus far, 12 functional TLRs have been identified in mice, and 10 in humans (Kawai and Akira, 2010; O’Neill, 2004). TLRs are localised in endosomal compartments (including TLR3, TLR7, TLR8 and TLR9), or are cell membrane bound (as with all other TLRs).
The central nervous system, once thought to be a site of immunological privilege, has since been found to harbour immunocompetent cells and to communicate with the peripheral nervous system. In the central nervous system (CNS), glial cells display immunological responses to pathological and physiological stimuli through pro- and anti-inflammatory cytokine and chemokine signalling, antigen presentation and the clearing of cellular debris through phagocytosis. While this neuroinflammatory signalling can act to reduce neuronal damage and comprises a key facet of CNS homeostasis, persistent inflammation or auto-antigen-mediated immunoreactivity can induce a positive feedback cycle of neuroinflammation that ultimately results in necrosis of glia and neurons. Persistent neuroinflammation has been recognised as a major pathological component of virtually all neurodegenerative diseases and has also been a focus of research into the pathology underlying psychiatric disorders. Thus, pharmacological strategies to curb the pathological effects of persistent neuroinflammation are of interest for many disorders of the CNS. Accumulating evidence suggests that GABAergic activities are closely bound to immune processes and signals, and thus the GABAergic neurotransmitter system might represent an important therapeutic target in modulating neuroinflammation. Here, we review evidence that inflammation induces changes in the GABA neurotransmitter system in the CNS and that GABAergic signalling exerts a reciprocal influence over neuroinflammatory processes. Together, the data support the hypothesis that the GABA system is a potential therapeutic target in the modulation of central inflammation.

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^*: Luke A.J. O'Neill has been a member of the Editorial Board of Trends in Immunology since 2003.

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Trends in Immunology

TLRs: Professor Mechnikov, sit on your hat

Section snippets

From endogenous pyrogen to TLRs

Can we believe the hype?

Where to now? Lampreys, negative signals and drugs

Concluding remarks

Acknowledgements

Cell

Cell

J. Biol. Chem.

Cell

Immunity

Microbes Infect.

Microbes Infect.

Curr. Opin. Immunol.

Curr Biol.

J. Biol. Chem.

Immunity

J. Biol. Chem.

Curr. Opin. Pharmacol.

Studies on the pathogenesis of fever. Characterisation of fever-producing substances from polymorphonuclear leukocytes and from the fluid of sterile exudates

J. Exp. Med.

cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily

Science

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Nature

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Cell

Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor κB

Proc. Natl. Acad. Sci. U. S. A.

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Eur. J. Biochem.

Signaling in plant–microbe interactions

Science

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

Nature

A family of human receptors structurally related to Drosophila Toll

Proc. Natl. Acad. Sci. U. S. A.

Signal transduction pathways activated by the IL-1 receptor family: ancient signalling machinery in mammals, insects and plants

J. Leukoc. Biol.

Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling

Nature

Defective LPS signalling in C3H/HeJ and C57BL/10ScCr mice: mutations in the TLR4 gene

Science

Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4)

J. Exp. Med.

Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors

Science

Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2

Science

The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens

Nature

IRAK: a kinase associated with the interleukin-1 receptor

Science

Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6

Oncogene

Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signalling cascades

Int. Immunol.