|Year : 2013 | Volume
| Issue : 2 | Page : 57-63
Toll-like receptors: A double edge sword
Mishal Piyush Shah1, Akash Prahlad Patel1, Priteshkumar Sureshchand Ganna2, Kinnari Mishal Shah3
1 Department of Periodontology, Narsinhbhai Patel Dental College and Hospital, Visnagar, India
2 Department of Orthodontics, Sidhpur Dental College and Hospital, Sidhpur, India
3 Private Practitioner, Mehsana, Gujarat, India
|Date of Web Publication||11-Feb-2014|
Mishal Piyush Shah
Department of Periodontology, Narsinhbhai Patel Dental College and Hospital, Visnagar
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Innate immunity is the first line of host defense and represents inherited resistance to infection. Innate immunity works through toll-like receptors (TLRs), which recognize the conserved molecular patterns on pathogenic bacteria known as pathogen-associated molecular patterns (PAMPs). The periodontium is a unique environment in which oral microorganisms are in constant contact with the host immune system. The TLRs present on gingival epithelial cells are continuously stimulated, resulting in production of cytokines and defensins that help to maintain oral health. If the epithelial barrier is breached, allowing invasion of bacteria into the underlying connective tissue, the TLRs on other resident and non-resident cells of the periodontium become activated. This leads to an exaggerated release of pro-inflammatory cytokines and other biological mediators, which may cause host tissue destruction.
Clinical Relevance to Interdisciplinary Dentistry
Protecting periodontium during and after the restoration is very important. since, periodontal tissues are in continuous contact with oral microorganisms and through that to the host immune system. The TLRs present on gingival epithelial cells are continuously stimulated, resulting in production of cytokines that help to maintain oral health. If the epithelial barrier is breached, during the restorative procedures or due to impinging restorations, allowing invasion of bacteria into the underlying connective tissue, which may cause host tissue destruction.
Keywords: Adaptive immunity, innate immunity, pathogenesis, periodontitis, signaling mechanism, toll-like receptors
|How to cite this article:|
Shah MP, Patel AP, Ganna PS, Shah KM. Toll-like receptors: A double edge sword. J Interdiscip Dentistry 2013;3:57-63
| Introduction|| |
Periodontitis is a chronic bacterial infection that affects the tooth-supporting structure. Bacterial plaque stimulates the host inflammatory response, leading to tissue damage. The immune response applies a family of pattern-recognition receptors (PRRs) called toll-like receptors (TLRs). It acts as a tool to trigger an inflammatory response to microbial invasion.
Toll gene products were first discovered in 1985 and were described as being critical for the embryonic development of dorsal-ventral polarity in the fruit fly, Drosophila. , In addition, the protein Toll mediates the immune response to fungal infection in Drosophila, and binding to this protein can induce the release of antimicrobial proteins.  In 1991, the sequence of the cytoplasmic domain of the Toll protein and the interleukin 1 (IL-1)-receptor were reported to be similar, which is consistent with involvement in the immune response.  This cytoplasmic domain is called the Toll-IL-1 receptor (TIR-1) domain. Subsequently, homologues of Drosophila Toll, the so-called TLRs, were identified in mammals.  Now, it is clear that TLRs function as key PRRs of the innate immune system.  They recognize and distinguish highly conserved structures present in large groups of microorganisms. The structures are referred to as pathogen-associated molecular patterns (PAMPs). Examples of PAMPs are bacterial lipopolysaccharide, peptidoglycan, lipoproteins, bacterial DNA and double-stranded RNA. In the innate immune system, TLRs sense invasion by microorganisms such as bacteria, viruses, fungi and protozoa, and trigger immune responses to clear such pathogens. Till now, 10 TLRs in humans and 12 TLRs in mice have been described.  On interaction with PAMPs, TLRs transmit this information through intracellular signaling pathways, resulting in activation of innate immune cells. The TLR-mediated innate immune response is also critical for the development and direction of the adaptive immune system. Thus, TLRs act as a double-edged sword, not only maintaining periodontal health (a positive edge) but also contributing to periodontal tissue destruction (a negative edge).
| The Toll-Like Receptor Superfamily|| |
TLRs, together with the IL-1 receptors, form a receptor superfamily known as the "Interleukin-1 Receptor/TLR Superfamily"; all the members of this family have in common a so-called TIR-1 domain. Three subgroups of TIR domains exist. Proteins with subgroup 1 TIR domains are receptors for ILs that are produced by macrophages, monocytes and dendritic cells, and all have extracellular immunoglobulin (Ig) domains. Proteins with subgroup 2 TIR domains are classical TLRs and bind directly or indirectly to molecules of microbial origin. A third subgroup of proteins containing TIR domains consists of adaptor proteins that are exclusively cytosolic and mediate signaling from proteins of subgroups 1 and 2. 
TLRs are present in vertebrates as well as in invertebrates. It has been estimated that most mammalian species have between 10 and 15 types of TLRs. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, although equivalents of certain TLRs found in humans are not present in all mammals. For example, a gene encoding a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus.  On the other hand, mice express TLRs 11, 12 and 13, none of which are represented in humans. Other mammals may express TLRs that are not found in humans.
| Structure of the Human Toll-Like Receptor|| |
Human TLRs respond to various PAMPs shared by numerous microorganisms. TLRs are transmembrane glycoproteins possessing varying numbers of extracellular N-terminal leucine-rich repeat (LRR) domains, followed by a cysteine-rich region, a transmembrane domain and a C-terminal cytoplasmic TIR domain [Figure 1].  The LRR domain is important for ligand binding and associated signaling, and is a common feature of PRRs. The TIR domain is important in protein-protein interaction, and is typically associated with innate immunity.
| Toll-Like Receptor Ligands and Signaling Mechanism|| |
Ilya Mechnikov, an immunologist and Nobel Prize winner in 1908, first recognized that upon rupture of the skin, phagocytes rapidly move to the affected area and take up foreign substances. This phenomenon is most likely triggered by TLRs. Innate immunity represents the first line of immunological defense. The main distinction between the innate and the adaptive immune systems lies in the receptors used for immune recognition. Historically, innate immunity has been suggested to mediate non-specific immune responses as a consequence of ingestion and digestion of microorganisms and foreign substances by neutrophils and macrophages. However, innate immunity is now recognized as showing remarkable specificity by means of discriminating between the host and the pathogens through a sophisticated TLR-based system.
Although TLR and IL-1-receptor cytoplasmic domains are homologous, the TLR extracellular domains differ. The IL-1-receptors contain three Ig-like domains, whereas the TLR extracellular domains are characterized by the frequency of LRR. The number of LRR in each of the 10 known human TLRs responds to distinctive PAMPs that characterize a microbial infection. Specificity for PAMPs is provided by a relatively limited repertoire of TLRs; combinations of TLRs are generally required for recognition of certain PAMPs. , Many human TLRs and their ligands are known [Figure 2], [Table 1].  TLRs can be classified as cell surface TLRs and intracellular TLRs [Table 2]. Cell surface TLRs seem to recognize microbial products whereas intracellular TLRs recognize nucleic acids [Figure 2].
Upon ligand binding, TLR-mediated signaling activates signal transduction, leading to transcription of pro-inflammatory cytokines that initiate innate immune responses critical for the induction of adaptive immunity.
TLR ligation initiates the interaction between TIR domains and cytoplasmic adaptor molecules [Figure 3]. Myeloid differentiation primary-response protein 88, a key adaptor molecule, is used by most TLRs. Myeloid differentiation primary-response protein 88 mediates the TLR-signaling pathway that activates IL-1-receptor-associated kinase. IL-1-receptor-associated kinase then associates with tumor necrosis factor (TNF) receptor-associated factor 6, leading to the activation of two distinct signaling pathways. One pathway leads to activation of activator protein-1 through activation of mitogen-activated protein kinase. The other pathway activates the transforming growth factor-b-activated kinase/transforming growth factor-b-activated kinase-1-binding protein complex, which enhances the activity of the inhibitor of nuclear factor-κB kinase complex. Once activated, this complex phosphorylates and induces subsequent degradation of the inhibitor of nuclear factor-κB and releases nuclear factor-κB, which translocates into the nucleus and induces expression of cytokines and chemokines. 
|Figure 3: Toll-like receptor (TLR) signaling pathways and TLR ligands derived from bacterial plaque microorganisms, AP-1: Activator protein-1, IKK: Inhibitor of nuclear factor-κB kinase, IRAK: Interleukin (IL)-1-receptor-associated kinase, IRF-3: Interferon (IFN)-regulatory factor-3, MAK: Mitogen-activated protein kinase, MyD88: Myeloid differentiation primary-response protein 88, NF-κB: Nuclear factor-κB, TAK1: Transforming growth factor-β-activated kinase 1, TIRAP: Toll-IL-1 receptor domain-containing adaptor protein, TLR: Toll-like receptor, TRAF6: Tumor necrosis factor-receptor-associated factor 6, TRAM: TRIF-related adaptor molecules, TRIF: Toll-IL-1 receptor domain-containing adaptor-inducing IFN-β, LPS: Lipopolysaccaride|
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TLR signaling cascades are separated into two groups: The myeloid differentiation primary-response protein 88-dependent pathway and the myeloid differentiation primary-response protein 88-independent pathway [Figure 3]. The myeloid differentiation primary-response protein 88-dependent pathway is essential for most TLR-mediated cell activations. Stimulation of TLR 3 or TLR 4, however, results in induction of type I interferon through interferon-regulatory factor-3 in a myeloid differentiation primary-response protein 88-independent manner. ,
The molecules that are structurally related to myeloid differentiation primary-response protein 88 led to identification of other adaptors, including:
- TIR domain-containing adaptor protein/myeloid differentiation primary-response protein 88-adaptor-like (TIRAP/MAL) ,
- TIR domain-containing adaptor inducing interferon-β (TRIF) 
- TRIF-related adaptor molecules (TRAM). ,
Specific TLR-mediated signaling pathways differentially select adaptors to initiate the myeloid differentiation primary-response protein 88-dependent or myeloid differentiation primary-response protein 88-independent pathway. A limited number of TLRs, acting through a restricted portal of only four adaptors, might differentially signal in response to a wide array of microbial products. As a result, clusters of many genes are selectively regulated to control needed immune processes. 
| Role of Toll-Like Receptors in Innate and Adaptive Immunity|| |
TLRs are predominantly expressed on cells of the innate immune system, including neutrophils, monocytes/macrophages and dendritic cells. These cells express different TLRs, allowing them to induce a wide variety of immune responses to specific pathogens. Neutrophils, the predominant innate immune cells in blood, express TLR 1, TLR 2 and TLR 4-TLR 10 [Table 3].  Being the first innate immune cells to migrate to the site of infection, neutrophils utilize relevant TLRs to recognize and respond to different types of microbial challenges. Like neutrophils, monocytes/macrophages are also considered as a first line of defense against microbial pathogens. They play a key role in host defense by recognizing, engulfing and killing microorganisms. Monocytes/macrophages express TLR 1, TLR 2 and TLR 4-TLR 8 [Table 3].  The binding of PAMPs to monocyte TLR can influence the type of adaptive immune response. A recent report shows that activation of TLR 2/1 on monocytes leads to their differentiation into macrophages rather than dendritic cells, resulting in a poor antigen-specific Th1 response. 
It is clear that development of adaptive immunity to pathogens is controlled through activation of innate immune cells, especially antigen-presenting dendritic cells. These "professional" antigen-presenting cells are derived from bone marrow and deployed throughout the body as immature cells. During infection, TLRs of resident immature dendritic cells detect the PAMPs on or released from invading microorganisms. Upon interaction with a pathogen, TLRs transmit information about the encounter through signaling pathways, resulting in activation of dendritic cells. This activation involves expression of co-stimulatory molecules and production of cytokines and chemokines, all of which are critical for T-cell priming and differentiation.  Dendritic cells express several TLRs. In human skin, two subsets of immature dendritic cells are found: Langerhans cells in the epidermis and interstitial dendritic cells in the dermis. In human blood, two subpopulations of dendritic cell precursors are present, which can be identified by cell phenotype and morphology. CD11c + dendritic cells are myeloid in appearance and express myeloid markers (CD13 and CD33), whereas CD11c - dendritic cells have negligible expression of myeloid markers and express high levels of the IL-3R (CD123).  As a result of their plasma cell-like morphology, CD11c - dendritic cells have been called plasmacytoid dendritic cells. ,, Human myeloid dendritic cells express TLR 1-TLR 6, TLR 8 and TLR 10 [Table 3]. In contrast, human plasmacytoid dendritic cells express TLR 1, TLR 6, TLR 7 and TLR 9 [Table 3]. , It is increasingly recognized that dendritic cells use TLRs to distinguish between different pathogens and initiate appropriate, effective types of immune responses. The TLR expression profiles of distinct dendritic cell subsets suggest a differential function in sensing pathogens and influencing an adaptive immune response. Inflammatory cytokines can trigger dendritic cell maturation but, without direct TLR stimulation, the dendritic cells fail to induce T helper cell differentiation.  Different TLR ligands instruct dendritic cells to stimulate distinct T helper cell responses. E. coli lipopolysaccharide and flagellin, which trigger TLR 4 and TLR 5, respectively, cause human dendritic cells to induce a Th1 response via IL-12 production. In contrast, the TLR 2 ligand, Pam3cys, and P. gingivalis lipopolysaccharide cause induction of a Th 2 response. ,
| Positive Edge of Toll-Like Receptors|| |
The periodontium is continually exposed to dental plaque, which harbors many commensal and pathogenic oral microorganisms. Periodontal tissues express different types of TLRs, allowing them to actively participate in the innate immune response against these oral microorganisms. Thus, these TLRs provide a first line of defense in maintaining periodontal health.
It has been suggested recently that the oral mucosa develops tolerance after repeated exposure to bacterial products.  Down-regulation of TLR expression and inhibition of intracellular signaling may be the underlying mechanisms of tolerance. However, recent research has indicated that under steady-state conditions, activation of TLRs by commensal bacteria is critical for the maintenance of oral health. Gingival epithelial cells express TLR 2, 3, 4, 5, 6 and 9 and recognize various microorganisms with the help of these receptors.  These TLRs expressed on the gingival epithelium continually interact with oral microorganisms that form biofilms on tooth surfaces. This TLR signaling results in innate immune responses involving the release of the antibacterial β-defensinscathelicidin and calprotectin, as well as neutrophil chemoattractant (IL-8). Therefore, TLR signaling limits microbial invasion and prevents commensal organisms from breaching the epithelial barrier, thereby maintaining gingival health.
Periodontal health represents a dynamic state in which pro-inflammatory and anti-microbial activities for control of infection are optimally balanced by anti-inflammatory mechanisms to prevent unwarranted inflammation. This homeostasis is disrupted when pathogens present in dental plaque undermine the host defense mechanism. Chronic stimulation of TLRs in periodontal tissues by bacterial PAMPs can lead to excessive production of pro-inflammatory mediators, resulting in tissue destruction. Also, periodontitis induced by bacterial plaque may start with disruption and penetration of the gingival epithelial barrier by invasive bacteria or their cytotoxic products. Through this invasion into deeper tissues, TLRs in other cells such as macrophages, fibroblasts, osteoblasts, osteoclasts and antigen-presenting cells become activated. These cells, when stimulated, produce various pro-inflammatory cytokines that lead to inflammation and immune cell infiltration. The infiltrated cells, such as memory T-cells, further produce cytokines and amplify the inflammatory reaction, leading to destruction of connective tissue and bone.
| Negative Edge of Toll-Like Receptors|| |
The first cells to respond to PAMPs are the epithelial cells lining the sulcus. These cells express intercellular adhesion molecule-1 (ICAM-1) and the ligand for lymphocyte function-associated antigen-1 (LFA-1), which interact with and direct the attachment and migration of leukocytes toward the gingival sulcus. IL-8, a known neutrophil chemoattractant, is also released by epithelial cells, further enhancing the migration of neutrophils.  Epithelial cells are also known to produce matrix metalloproteinases (MMPs) in response to PAMPs, causing direct damage to periodontal tissues.  Once the epithelial cells are activated, they mediate the activation of other resident as well as non-resident cells. When stimulated via TLRs, neutrophils exhibit increased chemotaxis as well as production of pro-inflammatory cytokines IL-1, IL-6, TNF-α).  These cytokines play a central role in periodontal tissue destruction. The properties of these cytokines that relate to tissue destruction involve stimulation of bone resorption and induction of tissue-degrading proteinases. The IL-8 secreted by epithelial cells stimulates the endothelial cells lining the blood vessels through TLR-4, leading to increased adhesion of monocytes by increased expression of the adhesion molecules E-selectin, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1).  When exposed to PAMPs, monocytes produce pro-inflammatory cytokines and may differentiate into osteoclasts upon direct stimulation with bacterial lipopolysaccharides with the help of receptor activator of nuclear factor κB ligand (RANKL). ,
Dendritic cells are resident immune cells present in both epithelium and connective tissue. TLRs present on these cells induce their maturation when stimulated with PAMPs. When activated, these cells not only act as antigen-presenting cells but also produce cytokines and co-stimulatory molecules that activate T-lymphocytes to produce a Th1 or Th2 immune response [Figure 4]. 
|Figure 4: Toll-like receptor-mediated effects of pathogen-associated molecular patterns on cells of the periodontium and their interactions. ICAM-1: Intercellular adhesion molecule-1, IL-1: Interleukin-1, IL-8: Interleukin-8, LFA-1: Ligand for lymphocyte function-associated antigen-1, LPS: Bacterial lipopolysaccharides, M-CSF: Macrophage colony-stimulating factor, MMPs: Matrix metalloproteinases, PDL: Periodontal ligament, RANKL: Receptor activator of nuclear factor kappa B ligand, TNF-α: Tumor necrosis factor-α|
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As the epithelial barrier is breached, microorganisms and their products access gain to the underlying connective tissue and directly activate the cells present there. Once stimulated by PAMPs, gingival fibroblasts produce pro-inflammatory cytokines leading to tissue destruction and bone resorption. Periodontal ligament fibroblasts, on the other hand, produce proteinases on TLR stimulation, resulting in direct degradation of periodontal tissues.  With the PAMPs entering the circulation via blood vessels in connective tissue, lymphocytes move toward the site of infection. In the presence of biological mediators, naïve T-cells differentiate and initiate a Th1 or Th2 immune response, TLRs on T cells acting as a type of co-stimulatory molecule.  B lymphocytes are transformed into plasma cells, which produce antibodies against bacterial antigens. Osteoblasts also react to PAMPs through TLRs and produce biological mediators (MMPs, prostaglandin E2) responsible for bone resorption. 
Osteoblasts, marrow stromal cells and T and B cells express RANKL, which is essential for activation of osteoclasts. RANKL in the presence of macrophage colony-stimulating factor (M-CSF) attaches to RANK present on osteoclasts and osteoclast precursors and activates them.  A bone-protecting factor, osteoprotegrin (OPG), produced by osteoblasts and bone marrow stomal cells, inhibits the RANK/RANKL interaction and prevents bone resorption. 
If the destructive process continues, more subgingival plaque tends to accumulate, connective tissue attachment to the tooth is destroyed, epithelial cells proliferate apically along the root surface and the periodontal pocket deepens. If not controlled, the bone and attachment loss extends to the apex and the tooth is ultimately lost.
| Conclusion|| |
TLR signaling at the dento-epithelial junction is critical in maintaining periodontal health as well as in the progression of periodontitis. However, there are still gaps in the knowledge of the mechanisms by which TLRs maintain periodontal health and what leads to bacterial immune evasion and disease progression. At present, it is uncertain which specific signaling pathways need to be blocked to attenuate the pathology or enhanced to promote host defense. Therefore, further investigations are required in this field to understand the initiation and progression of periodontal disease and develop therapeutic interventions to control it.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]