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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 1  |  Page : 1-4

Toll-like receptors: from bench to bedside


Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia

Date of Submission13-Nov-2014
Date of Acceptance26-Feb-2015
Date of Web Publication18-Mar-2016

Correspondence Address:
Shimaa S Mohamed El-Sayed
El-Sayed, MBBCh, Subk Al Ahad, Ashmun, 32858 Al Menoufia

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.178936

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  Abstract 

Objective
The aim of the work was to highlight toll-like receptors and their therapeutic use in different diseases.
Data sources
Data were obtained from medical text books, medical journals, and medical websites, which had updated investigations with the key word (toll-like receptors) in the title of the papers.
Study selection
Selection was carried out by supervisors for studying toll-like receptors and their clinical significance.
Data extraction
Special search was carried out for the key word toll-like receptors in the title of the papers, and extraction was made, including assessment of quality and validity of papers that met with the prior criteria described in the review.
Data synthesis
The main result of the review and each study was reviewed independently. The obtained data were translated into a new language based on the need of the researcher and have been presented in various sections throughout the article.
Recent findings
We now know that innate immunity plays an important role in the initiation of an immune response that follows the activation of antigen specific acquired immunity. A complete understanding of the mechanisms of innate immunity will be helpful for the future development of innovative therapies for the treatment of infectious diseases, cancer, allergies, and renal diseases.

Keywords: Clinical, innate immunity, signaling, toll-like receptors


How to cite this article:
Galal AZ, Alla Shoaib SA, Emara MM, Mohamed El-Sayed SS. Toll-like receptors: from bench to bedside. Menoufia Med J 2016;29:1-4

How to cite this URL:
Galal AZ, Alla Shoaib SA, Emara MM, Mohamed El-Sayed SS. Toll-like receptors: from bench to bedside. Menoufia Med J [serial online] 2016 [cited 2019 Sep 21];29:1-4. Available from: http://www.mmj.eg.net/text.asp?2016/29/1/1/178936


  Introduction Top


The history of toll-like receptors (TLRs) began with the discovery of phagocytic cells by Mechnikov in 1883, followed by the first description of what is now known as interleukin 1 receptor (IL-1R) in 1940, and toll/interleukin 1 receptor domain (TIR domain) [1].

TLR adapter molecules MyD88 and interleukin1 receptor associated kinase were first discovered in IL-1 signaling. Homology between IL-1RI and Drosophila toll was found in 1991, and this led to the discovery of human toll in 1997 [2].

In 1998, toll was discovered to be a receptor for lipopolysaccharide (LPS) [2]. The TLRs are surface molecules on eukaryotic cells that detect and respond to microbial infection. TLRs derive their name because of their homology to the Drosophila toll molecule, an important component of an antifungal defense mechanism [3].

TLRs belong to a class of molecules known as 'pattern recognition receptors'. The ligands for these receptors are components of pathogenic microbes and are often called pathogen-associated molecular pattern [4].

The first reported human TLR was described by Nomura et al. [5].

TLR signaling are divided into two distinct signaling pathways, My88-dependent and TRIF-dependent pathway. MyD88-dependent response occurs on dimerization of TLR, and is utilized by every TLR except TLR3 [6].

Discovery and identification of TLRs

Toll was first described for its involvement in innate immunity in Drosophila melanogaster. Fruitflies with mutant toll receptors demonstrated high susceptibility to fungal infection [7].

One year later, a mammalian homolog of the toll receptor (now called TLR4) was shown to induce the expression of genes involved in inflammatory response [8].

After the characterization of the first mammalian TLR, TLR4, several proteins that are structurally related to TLR4 were identified and named TLRs [9].

Mammalian TLRs comprise a large family consisting of at least 11 members. TLR1-TLR9 are conserved between the human and mouse. However, although TLR10 is presumably functional in humans, the C-terminal half of the mouse TLR10 gene is substituted to an unrelated and nonproductive sequence indicating that mouse TLR10 is nonfunctional. Similarly, mouse TLR11 is functional, but there is a stop codon in the human TLR11 gene, which results in a lack of production of human TLR11 [10].

TLR signaling

Stimulation of TLRs by microbial components triggers expression of several genes that are involved in immune responses [11].

The molecular mechanisms by which TLRs induce gene expression are now rapidly being elucidated through analyses of TLR-mediated signaling pathways [11].

TLR signaling consists of at least two distinct pathways: MyD88-dependent pathway, which leads to the production of inflammatory cytokines, and MyD88-independent pathway, which is associated with the stimulation of interferon-b and the maturation of dendritic cells (DCs). MyD88-dependent pathway is common to all TLRs, except TLR3 [12].

MyD88 is essential for inflammatory cytokine production through all TLRs. A database search for molecules that are structurally related to MyD88 led to identification of the second TIR domain-containing molecule TIRAP (TIR domain-containing adapter protein)/Mal (MyD88-adapter-like) [13].

Similar to MyD88-deficient macrophages, TIRAP/Mal-deficient macrophages show impaired inflammatory cytokine production in response to TLR4 and TLR2 ligands [14].

MyD88-independent component exists in TLR4 signaling. Subsequent studies have demonstrated that TLR4 stimulation leads to activation of the transcription factor interferon regulatory factor 3 (IRF-3), as well as the late phase of nuclear factor k light chain enhancer of activated B cell (NF-kB) activation, in a MyD88-independent manner [15].

TLRs in therapy

In recent years, the identification of several TLR mutations and common polymorphisms has made it possible to determine their role in susceptibility to infection, and they have been associated with many other noninfectious diseases [16].

Moreover, microorganisms have been known to downregulate TLR activation, presumably to promote pathogen survival. The vaccinia virus genome encodes proteins that prevent NF-kB activation by TLRs, including TLR3, by inhibiting the interactions of interleukin1 receptor associated kinase and tumor necrosis factor receptor associated factor 6 [1].

Bacteria of Yersinia spp. secrete a protease, YopJ, that inhibits NF-kB activation and impairs TLR-mediated cell survival signals, but not proapoptotic signals, resulting in TLR-mediated induction of macrophage apoptosis [6]. These bacteria additionally use virulence factors to induce a TLR2-mediated, IL-10 dependent, anti-inflammatory response [17].

Mycobacteria have mechanisms to inhibit effective antigen presentation, as lipoarabinomannan (Is a lipoglycan and major virulence factor in the bacteria genus Mycobacterium) binding to DC lectins inhibits TLR-mediated cell maturation [18].

Reduction of excess inflammation - for example, in the context of septic shock - by downregulating TLR responses is a feasible therapeutic goal [19].

TLR4-/- mice are resistant to the effects of systemic endotoxin lipodisaccharide or lipid A from Rhodobacter sphaeroides, and the synthetic lipodisaccharide, E5564, prevents activation of human TLR4 by LPS, offering the possibility of new treatment methods for septic shock [20].

Microbial targeting of intracellular signaling illustrates other approaches that could be adapted to become viable pharmaceuticals. There are numerous other inflammatory diseases in which TLR activation may be important. In diseases such as atherosclerosis or some arthritides, involvement of infectious agents in disease initiation has been proposed, but intervening at disease initiation would require a degree of prescience we do not yet possess. Nonetheless, in these diseases, TLR signaling may be important in disease progression, if infectious agents show persistence, or if endogenous damage signals are acting in a TLR-dependent manner. The association of genetically impaired TLR4 function with a decreased risk for atherosclerosis supports such a hope [21].

TLR activators are extremely potent adjuvants, acting on DC to drive typical Th1 type responses during Ag presentation. Contrary to expectations, TLR4-/- mice also showed a role for TLR4 in driving Th2 cytokine generation through modulation of DC costimulatory molecule expression [22].

LPS stimulation amplified Th2 responses in a mouse model of allergic airway inflammation [23].

Some data also suggest that TLR2 activation can favor Th2 phenotypes by induction of IL-12 p40 homodimers and a reduced capacity for production of bioactive IL-12 p70 [24].

Nonetheless, the general trend for TLR activation to favor Th1 suggests that activation of these receptors in the context of allergen presentation may be exploited to augment allergen desensitization therapies, or perhaps antitumor responses. Imidazoliquones, synthetic compounds that may have a therapeutic range against a variety of viruses and parasites, activate TLR7 and TLR8 [25].

Th1-inducing activities also have potential adjuvant roles in human therapeutics [26].

In the context of allergen desensitization, interest has been focused on the potent Th1-driving abilities of cytosine phosphate guanosine (CpG) motifs acting through TLR9; the direct conjugation of CpG oligonucleotides to allergen may be a potent stimulus for causing allergen desensitization while minimizing potential CpG side effects [27].

Similarly, the finding that vaccine-enhanced respiratory syncytial virus disease can be mitigated by administering the vaccine together with a nontoxic TLR4 agonist, monophosphoryl lipid A, also provides an example of TLR4 manipulation to prevent disease [28].


  Conclusion Top


TLRs play a crucial role at all stages of the inflammatory responses and in tissue repair and regeneration. The possibility of modulating these stages through TLRs has opened an array of opportunities to develop innovative vaccines and therapies for the prevention and treatment of infectious and noninfectious inflammatory disorders. Many of these therapies are currently being evaluated in clinical trials. However, although TLR-based therapies have enormous biological potential and offer promising results, their benefits are not free of risk, and further research is required before drugs enter the trial phase and routine clinical practice.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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