How many tlrs

DAMPs include intracellular proteins such as heat shock proteins as well as protein fragments from the extracellular matrix. Signaling by TLRs result in a variety of cellular responses including the production of interferons IFNs , pro-inflammatory cytokines and effector cytokines that direct the adaptive immune response.

The structure of the extracellular domain of TLR3 was revealed by crystallography studies as a large horseshoe-shape [2]. TLRs are predominantly expressed in tissues involved in immune function, such as spleen and peripheral blood leukocytes, as well as those exposed to the external environment such as lung and the gastrointestinal tract.

Their expression profiles vary among tissues and cell types. TLR2 is essential for the recognition of a variety of PAMPs from Gram-positive bacteria, including bacterial lipoproteins, lipomannans and lipoteichoic acids.

TLR4 is predominantly activated by lipopolysaccharide. TLR11 12 has been reported to recognize uropathogenic E. The repertoire of specificities of the TLRs is apparently extended by the ability of TLRs to heterodimerize with one another. Individual TLRs induce different signaling reponses by usage of the different adaptor molecules. They involve the interferon regulatory factors, IRFs, a family of transcription factors known to play a critical role in antiviral defense, cell growth and immune regulation.

Significant progress has been made over the past years in the understanding of TLR function [20]. TLRs are essential receptors in host defense against pathogens by activating the innate immune system, a prerequisite to the induction of adaptive immune responses.

Although TLR-mediated signaling is paramount in eradicating microbial infections and promoting tissue repair, the regulation must be tight. TLRs are implicated in a number of inflammatory and immune disorders and play a role in cancer [21].

Many single nucleotide polymorphisms have been identified in various TLR genes and are associated with particular diseases. Several therapeutic agents targeting the TLRs are now under pre-clinical and clinical evaluation [22]. In fact, many ligands with distinct PAMPs exist, and the list of known ligands keeps growing.

Scientists have deduced the three-dimensional structure of TLRs with x-ray crystallography example, Figure 2b. The analysis of protein tertiary structure is a complicated puzzle, and figuring out the structure of something like a TLR is always a significant accomplishment.

For TLRs, the precise molecular details reveal how ligand-receptor interactions emerge from the properties of atoms within the receptor Jin et al. This information explains the specificity of a receptor and permits design of chemical agonists, which mimic the ligand's function, or chemical antagonists, which block the ligand's action. For example, chemists can use the molecular structure of TLR4 and its interaction with LPS to infer the best design for TLR4 antagonists, which can be treatments for certain inflammatory disorders, including sepsis Park et al.

TLRs 1, 2, 4, 5, and 6 are located primarily in the plasma membrane, where they interact with components of microbial pathogens that come into contact with the cell. In contrast, TLRs 3, 7, 8, and 9 are situated in the membranes of endosomes and lysosomes; the extracellular domain of the receptor and its ligand-binding site project into the interior of these organelles. TLRs have complex expression patterns in different cell types.

Recall that different cell types of a multicellular organism share the same set of genes, but specialization of cell function is possible because different genes are expressed.

TLR expression is particularly significant in different types of white blood cells: mast cells, macrophages, and dendritic cells. These cells leave the bloodstream and take up residence in tissues throughout the body, where they are detectors of pathogens. Innate immune responses are initiated by mast cells and macrophages, whereas adaptive immune responses are primarily initiated by dendritic cells.

There is an unexpected twist to the story of TLRs. Most scientists assumed that TLR function is specialized to detect foreign organisms so that the body can distinguish self from nonself.

However, there is now convincing evidence that some TLR ligands originate from the host. Why would the immune system react to self-components? The hypothesis is that these new ligands act as damage signals damage-associated molecular patterns, or DAMPs to alert the body of cell and tissue injury. Many injuries result in a messy form of cell death called necrosis, which releases intracellular components into the surroundings, and some of these components specifically activate TLRs Yang et al.

Breakdown products of the extracellular matrix may also act as damage signals Schaefer Scientists are still speculating on the purpose of these endogenous signals. They might initiate tissue repair responses, initiate immune responses as a preemptive strike against infections that usually follow injury, or collaborate with TLRs to identify pathogens that cause injury and distinguish them from harmless commensal microbes. Endogenous damage signals can stimulate an inappropriate innate immune response that does more harm than good in some cases in which there is no infection.

An example is ischemic injury that results from the temporary loss of blood flow and hence oxygen supply. Ischemic injury is a concern in many clinical scenarios, including stroke and transplantation. Cell death during ischemia releases damage signals, and restoration of blood flow allows an influx of white blood cells, which cause inflammation in response to the signals.

This inflammation leads to more destruction than the original injury. There is also evidence that TLRs contribute to the development of atherosclerosis and Alzheimer's disease through sensing of damage signals in the form of oxidized lipoproteins Stewart et al.

After TLRs detect pathogen or damage-associated molecular patterns, they must convert these signals into messages inside a cell via signal transduction Figure 2c. Often, it is these signaling events that scientists want to change when they consider designing drugs for disease intervention.

Signaling components inside a cell called protein kinases activate other proteins by adding a phosphate group to certain amino acids, and they are among the best characterized drug targets. Approximately ten protein kinase inhibitors have already been approved for the treatment of cancer.

For example, mice are resistant to septic shock and chronic inflammation if they have a defective form of IRAK4 Cohen ; thus, inhibitors of IRAK4 may help prevent septic shock and inflammation in humans. The final response of a cell to TLR stimulation usually involves activation of transcription factors that regulate specific patterns of gene expression , leading to an increased production of hundreds of proteins.

They include small proteins called cytokines, which are secreted from the cell to recruit and activate other cells, thus initiating and orchestrating the wider immune response. Vaccines for diseases such as AIDS, hepatitis C, malaria, and even cancer might be made more effective by supplementing them with TLR activators that stimulate dendritic cells.

The activated dendritic cells then produce a more effective adaptive immune response. For example, scientists have linked a conserved component of influenza viruses with an agonist to TLR5 to create a vaccine that could potentially protect against all strains of flu Huleatt et al. Beck, G.

Immunity and the invertebrates. Scientific American , 60—66 Blasius, A. Intracellular Toll-like receptors. Immunity 32 : — Cohen, P. Targeting protein kinases for the development of anti-inflammatory drugs. Current Opinion in Cell Biology 21 , — doi: Gill, R. Linking oxidative stress to inflammation: Toll-like receptors.

Free Radical Biology and Medicine 48 , — doi Hashimoto, C. The Toll gene of Drosophila , required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52 , — doi Hennessy, E. Targeting of Toll-like receptors: Emerging therapeutics?

The anti-pathogen pathway of S. The phylum Cnidaria is a morphologically primitive outgroup to bilaterians and comprises approximately 10, aquatic organisms, including corals, Hydra , sea anemones, and jellyfish In addition, two transmembrane TIR domain-containing proteins and two LRR domain-containing proteins have been identified in Hydra 34 — Therefore, flagellin may be the ligand of HyLRR-2 initiating innate immune signaling.

Studies on Hydra have also suggested a role for its canonical TLR pathway in pathogen defense, as silencing of a TIR domain-containing protein resulted in a loss of antimicrobial peptide production, and Hydra became more sensitive to Pseudomonas aeruginosa infection when MyD88 was silenced 34 , Two TIR domain-only genes have been identified in the genome of the sea anemone Exaiptasia pallida ; they may encode the same protein 36 , Nevertheless, little is known about the specific downstream signaling pathway or the ligand responsible for Nv-TLR involvement in the developmental and immune processes 39 , Further, O.

The roles of platyhelminth TLRs have mainly been explored in planarians, turbellarians, and rotifers. As non-parasitic flatworms, Planarians are of great evolutionary importance for the analysis of injury-induced immune responses and the regeneration process in metazoans 46 , However, the exact mechanisms and underpinning signaling networks require further investigation.

Furthermore, immune responses or pathways in rotifers have not been reported. Hence, a comprehensive elucidation of the immune responses initiated by TLRs against pathogens, or PAMP stimulation and the mechanisms involved in the phylum Platyhelminthes should be conducted in the future.

Caenorhabditis elegans is a classic model organism for the study of nematodes. It has been demonstrated that C. Although previous studies have shown that TOL-1 is important for early development and pathogen recognition in C.

Recently, Brandt and colleagues revealed that TOL-1 contributes to the development and function of BAG neurons required for the pathogen-avoidance behavior in C. In addition, C. Single P-type TLRs have also been identified in Caenorhabditis briggsae, Caenorhabditis brenneri , and Caenorhabditis japonica 51 , 61 — However, the associated-downstream pathways or functions of these TLRs have not been elucidated. Given that the sequences of TLRs among Caenorhabditis species are conserved 63 , we speculate that the biological roles of these proteins are similar to those elucidated in C.

Davidson and colleagues presented preliminary evidence for the existence of TLRs in the genomes of annelids, including polychete worm Capitella capitata and leech Helobdella robusta They identified 16 and TLRs loci in the H. Notably, the sequences of TLRs in C.

Another study has revealed that differentiated H. Notably, the regeneration of severed nerve cords appears to proceed more rapidly upon pathogen stimulation, which may be associated with the Hm-TLR1-induced upregulation of pro-inflammatory cytokine p43 66 , Overall, these results indicate that annelid TLRs play vital roles in neurogenesis and neuroimmunity.

Until now, several TLRs have been identified in molluscan species, including Crassostrea gigas, Biomphalaria glabrata, Chlamys farreri , and Cyclina sinensis.

There are 56 TLR-encoding genes in B. In addition, it has been reported that Bg-TLR is dramatically overexpressed in hemocytes upon PAMP stimulation, and its knockdown impairs the hemocyte phagocytic activity 70 , In addition, the expression of P-type CgToll-1 is induced during Vibrio anguillarum infection Similarly, treatment of C. Furthermore, infection of C. These results indicate that MyDdependent signaling pathway is involved in the activation of downstream immune reactions in C.

The interaction between the TIR domain of C. The CfTLR network also plays a role in hemocytes, as the expressions of pathway components, as well as that of four LRR-domain containing proteins, are induced upon exposure to several pathogens 77 , Collectively, these results indicate that the TLR signaling network of C. Furthermore, molluscan TLRs likely play an important role in molluscan development, as demonstrated by the upregulation of three C.

However, there have been relatively few studies concerning the developmental roles of molluscan TLRs and thus, further studies are essential to elucidate these issues.

Toll-like receptors in Merostomata species have been, to date, investigated by relatively few studies. A TLR gene tToll , with the length and architecture comparable with that of Toll-1 of Drosophila , has been identified in the horseshoe crab Tachypleus tridentatus Coagulin reportedly enhances the dimerization of tToll and induces the activation of intracellular cascades With more than a million species, Insecta is by far the largest group of hexapod invertebrates within Arthropoda.

Upon infection, insects can rapidly mount an antimicrobial response involving cells, components, and processes, such as hemocytes, antimicrobial cytokines, and melanization, respectively 85 — The insect antimicrobial response appears to be similar to the mammalian innate immune response To date, studies of the model species D.

It has been reported that the innate immune response of D. In particular, studies have indicated that the Toll pathways are involved in the induction of expression of antimicrobial peptides in D. Thereafter, genes for other Toll family members Toll-2—9 were detected in the genome of D. Imler and Hoffmann have reported that, with the exception of Toll-9, all Toll proteins possess 1—4 additional cysteine-rich motifs In contrast with mammalian TLRs, D.

To date, several TLRs have been identified in crustacean species, including crabs, shrimps, and copepods. Among these, TLRs in shrimps, including Litopenaeus vannamei, Procambarus clarkii, Penaeus monodon, Fenneropenaeus chinensis, Macrobrachium rosenbergii , and Marsupenaeus japonicus , are the most extensively studied — Yao and colleagues revealed that genetic polymorphisms of TLRs are linked to the immune response to pathogen infections in L.

Recently, a Toll-9 receptor, PmToll9, has been identified in P. However, the mechanisms underlying the role of PmToll9 in defending the host against pathogens and mediating the innate immunity require further exploration. Studies of TLRs in crabs have mostly focused on mud crabs, including Scylla paramamosain, Scylla serrata , and the Chinese mitten crab Eriocheir sinensis — Challenge of S.

In addition, a single-nucleotide polymorphism mutation c. In addition, it has been reported that TLR signaling pathway-related genes in Caligus rogercresseyi are highly expressed at the chalimus and adult stages, promoting a more developed immune response Echinoderms are the most evolutionarily advanced invertebrates and share the evolutionary history with chordates.

TLRs reportedly play a pivotal role in the immunity of metazoans, including echinoderms, such as sea urchins and sea cucumbers Analysis of the entire genome of sea urchins, especially that of the purple sea urchin S. The innate receptor repertoire of S. Overall, TLR-like genes have been detected in the S. Buckley and colleagues reported that even though only 68 TLR-like gene sequences were found in Lytechinus variegatus , majority of the TLR subfamilies and homologous sequences identified in S.

In addition, analysis of the S. In echinoderms, it appears that members of the TLR3 family are specifically responsive to viral dsRNA associated with viral infection, whereas TLR4 receptor subfamily members are particularly responsive to LPS stimulation In echinoderms, studies have also focused on the TLRs of Apostichopus japonicas. It has been reported that the structures of AjMyD88 and AjTRAF6 and those of MyD88 and TRAF6 proteins of other species are highly conserved, and that the expression of genes encoding these two proteins is significantly upregulated following stimulation with Vibrio splendidus A recent study of A.

Evolutionarily placed at the invertebrate—vertebrate transition point, amphioxus, a typical cephalochordate, represents an important organism for research into understanding the evolution of the TLR-associated immune system Subsequently, an immune-associated TLR1 that participates in the defense against certain pathogens has been identified in Branchiostoma belcheri tsingtauense bbt Collectively, these findings provide reference for studying the complexity of the amphioxus innate immunity and indicate new perspectives for the related studies of vertebrates.

Non-mammalian vertebrates include organisms from the classes Cyclostomata, Chondrichthyes, Osteichthyes, Amphibia, Reptilia, and Aves. To date, at least 28 functional TLRs have been identified in various species from these classes. Members of the sixth major subfamily, the TLR11 subfamily, containing TLR11, 12, 13, 19—23, and 26, have multiple functions, which range from sensing proteins to nucleic acid motifs.

Cyclostomata, the lowest class of vertebrates, consists of two families of surviving jawless fish, the lampreys and hagfish Interestingly, TLR14 is a member of the TLR1 subfamily, and the encoding gene which is present in the genomes of teleosts and amphibians 21 , , suggesting that the current vertebrate TLR subsets emerged before the mammalian ancestor diverged from the jawless fish ancestor The expression of latlr14a is restricted to the gill, while the expression of latlr14b is observed in the skin, gill, heart, liver, gut, and leukocytes Subcellular localization analysis indicates that laTLR14a and 14b are largely localized in the endoplasmic reticulum, with only a small fraction found in other organelles.

However, whether this type of innate immune signaling occurs in the Japanese lamprey in vivo , and the identities of PAMPs necessary for activation and the adaptors involved, await further elucidation.

The repertoire of the 16 predicted lamprey TLRs has been determined. Hence, the IFN induction pathway may have originated in a common ancestor of jawed vertebrates. Jawed cartilaginous fish Chondrichthyes represent an important group of animals for immune-related research. They are considered to be the first species to have evolved adaptive immune responses. Further, the presence of the innate immune system at this evolutionary turning point is intriguing.

However, relatively few studies have focused on the TLRs of cartilaginous fish and, accordingly, there is a need to fill the gaps in the current knowledge about this group. TLR2 of C. Further protein modeling analysis indicated that C. However, the exact functions of these shark TLRs and their PAMP repertoire, as well as the induced signaling pathways require further experimental verification.

Osteichthyes, also referred to as teleost fish, comprise a remarkably diverse group of more than 23, species Among these, the structural and functional properties of TLR1—3, 5, and 7—9 are similar to those of their mammalian counterparts, whereas teleost TLR4 appears to be structurally conserved, but does not recognize LPS, unlike in mammals.

As mentioned above, vertebrate TLRs can be divided into six major subfamilies In mammals, TLR1 is involved in the recognition of triacylated lipoproteins and mycobacterial products by binding to TLR2 to form a heterodimer Teleost TLR1 and TLR2 have been characterized in Tetraodon Tetraodon nigroviridis , pufferfish Takifugu rubripes , zebrafish Danio rerio , , Japanese flounder Paralichthys olivaceus , channel catfish Ictalurus punctatus , , rainbow trout Oncorhynchus mykiss , , orange-spotted grouper Epinephelus coioides , large yellow croaker Pseudosciaena crocea — , rohu Labeo rohita , common carp Cyprinus carpio , and grass carp Ctenopharyngodon idella TLR2 signaling plays an important role in the activation of intestinal immune system in mammals According to a recent study, the TLR2 signaling pathway may be involved in the recognition of probiotic Psychrobacter sp.

TLR18 is an extensively expressed fish-specific TLR that plays a key role in the innate immune responses in teleosts It has been identified in many species, including channel catfish , zebrafish , grass carp , yellow catfish Pelteobagrus fulvidraco , Atlantic salmon Salmo salar , Japanese sea bass Lateolabrax japonicus , and Atlantic cod Gadus morhua TLR25 belongs to the TLR1 subfamily, and in addition to catfish, has also been found in Nile tilapia Oreochromis niloticus , fat head minnow Pimephales promelas , ayu Plecoglossus altivelis , and medaka Oryzias latipes.

TLR27 was first identified in the coelacanth Latimeria chalumnae Wang and colleagues recently reported its expression in spotted gar Lepisosteus oculatus , which indicates that TLR27 is highly evolutionarily conserved. Analysis of its characteristics revealed a high homology with TLR2. The protein is highly expressed in the liver of miiuy croaker, and after stimulation with V.

In a recent study, Jung and colleagues show that in rock bream Oplegnathus fasciatus , poly I:C exerts a biological effect by interacting with TLR3. Presently, TLR3 has been identified in various fish species: zebrafish , rainbow trout , common carp , rare minnow Gobiocypris rarus , grass carp , large yellow croaker , Japanese flounder , and sea perch L.

However, LPS recognition and sensitivity in fish are fundamentally different from those in mammals. Fish are often resistant to the exotoxin LPS Sepulcre and colleagues have reported that the sequenced fish genomes lack the genes of co-stimulatory molecules MD2 and CD Additionally, the majority of teleost species have lost TLR4 after separation from the mammalian lineage. Whole-genome sequencing of pufferfishes both T.

This may partially explain why fish are resistant to endotoxin and supports the speculation that the TLR4—LPS signaling network appeared after the divergence of fish and tetrapods. Huang and colleagues have identified four tlr4 genes in grass carp, which differ with respect to genomic structures and protein domains The expression of these four tlr4 genes is detected 12 h post-fertilization, and is significantly upregulated in the muscle and liver of adult grass carp after infection with grass carp reovirus GCRV , indicating that these TLR4 homologs may play immune functions during GCRV infection.

This implies that ligand specificities of TLR4 proteins of grass carp are different from those of mammalian TLR4, and provides important clues for the evolutionary scenario of TLR4. In recent years, TLR5M and TLR5S, which are present in many tissues , , , have been identified in pufferfish , orange-spotted grouper , Atlantic salmon , Japanese flounder , , catfish , Tibetan schizothoracine fish , , and turbot TLR5M is ubiquitously expressed in teleosts, with relatively high expression levels in the head kidney, spleen, liver, and brain tissues, whereas TLR5S has been detected mainly in the liver Two heterodimers form a stable complex via tail-to-tail binding that is stabilized by quaternary contacts of the FliC D1 domain with the convex surface of the opposing TLR5 and then induces MyDdependent signaling , In recent years, TLR7—9 have been identified in channel catfish , Atlantic cod , Tibetan schizothoracine fish , common carp , zebrafish , rainbow trout , grass carp , , Atlantic salmon , , yellow catfish , turbot , flounder , and sea bream After 8-week infection with the pathogen Mycobacterium marinum , the expression of TLR7 in the blood and lymphoid tissues of zebrafish is reduced, whereas the expression of TLR8 is elevated These differences in expression patterns may be related to the type of fish and different mechanisms of regulation in vivo and in vitro.

Studies on the TLR9 genes in common carp , large yellow croaker , and gilthead sea bream have indicated that TLR9 is mainly expressed in the kidney and spleen tissues, and that its expression increases following V. Distinct expression patterns of TLR8 and TLR9 have been observed in the mucosal tissues the intestine, gill, and skin of turbot after infection with V.

Given that the genes for the fish TLR7 subfamily respond to both viral stimuli and bacterial infections, it is possible that their functional differentiation may not be as precise as that of mammalian TLR7 subfamily members. Wang and colleagues were the first to report that in Perciformes particularly Sciaenidae , the teleost TLR13 is highly expressed in such immune defense-related tissues as the spleen, liver, and kidney Subsequently, TLR13 was identified in orange-spotted grouper, with relatively high expression levels in the brain and immune-related tissues, and was also found to be significantly upregulated in grouper spleen cells, indicating that TLR13 may be involved in the recognition of bacterial RNA When challenged with poly I:C or Aeromonas hydrophila , TLR22 is upregulated in a variety of common carp tissues , indicating an important role of TLR22 in systemic as well as mucosal defense after viral or bacterial infection.

Transcript levels of TLR22 are increased in response to bacterial-borne PAMPs and extracellular dsRNA in the euryhaline teleost Asian sea bass, with the highest expression observed in the kidney and liver However, the mechanisms underlying TLR11 subfamily function in fish require further investigation. The TLR14 subfamily appears to have been lost in amniotes but is expanded in amphibians. Therefore, Xenopus TLR4 might not be responsible for the bacterial exotoxin-initiated signaling pathway.

They also confirmed that genes of these TLRs are ubiquitously expressed in both tadpole and adult frog The role of TLR signaling pathway in dorsoventral patterning , and the involvement of MyD88 in the Spemann organizer formation have been reported in Xenopus laevis , suggesting that the TLR signaling is also essential for amphibian development Recently, an adaptor molecule MyD88 of Rana dybowskii was cloned and analyzed, and shown to contain a death domain and a TIR domain The structure of MyD88 in R.

Moreover, the expression of CgsTLR7 is upregulated in the liver, kidney, and spleen in response to a giant salamander iridovirus infection, indicating that CgsTLR7 plays vital roles in innate immunity As the only poikilothermic amniotes, reptiles have a unique physiology and occupy a central position in vertebrate evolution.

However, the structure, function, and ligand specificity of TLRs in reptiles have not been characterized Searches for reptilian TLR sequences have identified these in only one species, the green anole lizard Anolis carolinensis , which have been annotated as molecules resembling mammalian TLR2, 3, 4, 5, 6, 7, and Recently, Voogdt and colleagues reported the cloning, characterization, and functional analysis of TLR5 from A. Although diverged about million years ago, the immune responses of avian are broadly similar to those of mammals , Most of the knowledge of avian immunology was generated by studies of the junglefowl G.

To date, much has been learned about avian TLRs with regards to the recognized ligands. Avian genome analysis has more recently been extended from G. A study conducted to characterize TLRs in seven distantly related avian species— Carpodacus mexicanum Fringillidae , Falco naumanni Falconidae , Accipiter cooperii Accipitridae , Oceanodroma leucorhoa Hydrobatidae , Amazona albifrons Psittacidae , Dromaius novaehollandiae Casuariidae , and Picoides pubescens Picidae —revealed that avian TLRs appear to be characterized by purifying selection, although positive selection patterns have acted on specific amino acid residues.

Moreover, many positively selected positions have been mapped to putative ligand-binding regions, indicating that the variations are related to species-specific differences in the recognition of PAMPs Later, canonical TLRs were identified in Cnidaria 34 , while the ancestral type still exists until the phylum Annelida A Big Bang expansion of V-type TLRs was reported in many invertebrates including sea urchin and amphioxus via specific gene duplication , , which may be associated with the variation of life cycles, lifetimes, or environments.

This could be explained by the process of diversifying selection, as the LRR domain is responsible for pathogen recognition and its diversity is most likely caused by the positive selection of pathogens. During the life time of invertebrates, those closely related but diversified variants of TLRs could respond to the enormous and quickly evolving pathogens, and even the change of environments.

However, further functional characterization of those TLRs still needs to verify this hypothesis. Most invertebrate TLRs play dual roles and participate in both, developmental processes and immune responses against pathogens Table 1.

However, the function of vertebrate TLRs is specific to immunity, except for amphibians, where it is involved in dorsoventral patterning and Spemann organizer formation. At least 28 TLRs has been identified in vertebrates and can be divided into six major subfamilies Table 2.

Although some TLRs are not present in mammals, they nevertheless share high structural and functional similarities with mammalian TLRs. Compared with other vertebrates, teleosts and amphibians have the most complex TLR repertoire. Such expansion may be associated with the diversity of aquatic pathogens and the complexity of aquatic environment 22 , — Since the first appearance of TLR in porifera, the animalia has witnessed the development and evolution of TLRs for million years Figure 1.

Two important questions could be raised regarding the TLR evolutionary scenario. What is the driving force of TLR evolution? What caused the expansion of TLRs in invertebrates and the further contraction in vertebrates? We believe that stress maybe one of the main driving forces in the development of TLRs. For example, TLR3, 7, and 8 have important roles in the recognition of allergens and subsequently pathogenesis of allergic diseases as allergic rhinitis Golshiri-Isfahani et al.

It has been demonstrated that endosomal TLR7 and 9 are found to be overexpressed in SLE associated with the production of autoantibodies Subramanian et al. Upregulation of some TLRs has been shown in many tumor cells, tissues, and tumor cell lines. TLRs can recognize circulating DAMPs released from the dying cells and damaged tissues to trigger the process of self-healing and tissue repair Gauthier et al.

In atherosclerosis, TLR2 or 4 suppression resulted in diminishing inflammation in mouse models of atherosclerosis. TLR3 activation has been found to promote atherogenic inflammation, especially in mediating plaque instability Ishibashi et al. In hypertension, TLR4 has been well-documented to mediate inflammation in vasculature McCarthy et al. Excessive TLR activation can lead to systemic inflammation, characterized as sepsis.

TLR2 and 4 are the two sponsors to the pathogenesis of sepsis. Activation of TLRs was also reported to contribute to the development and progression of atherosclerosis, cardiac dysfunction, and congestive heart failure in sepsis Tsujimoto et al. Obesity and T2DM are known to be associated with chronic low-grade inflammation called metabolic inflammation together with an oxidative stress milieu found in the expanding adipose tissue Donath et al.

Therefore, TLR2 is significantly involved in diabetes progression Sepehri et al. TLR4 signaling pathway is involved in chronic inflammation and insulin resistance, which are associated with obesity and T2DM Jialal et al. Thus, TLR10 may represent an immune marker for metabolic inflammation Sindhu et al. A high-glucose level could also induce TLR-2 and TLR-4 expression in retinal ganglion cells via increase in the secretion of pro-inflammatory factors in diabetic retinopathy Zhao et al.

Both of them inhibit MyDdependent pathway Brint et al. Although TLRs are essential elements in innate immune system and play a critical role in the host-defensive mechanism against microbes, overactivation of TLRs disrupts the immune homeostasis leading to excessive pro-inflammatory cytokines production that is no doubt involved in the pathogenesis of many autoimmune and inflammatory diseases.

Thus, inhibition of TLR signaling pathways has been predicted to be an effective therapeutic strategy to suppress unwanted, disease-associated inflammatory responses Gao et al. Accordingly, various therapeutic agents for inhibiting TLR signaling have been developed to control excessive inflammation; they can be classified as small molecule inhibitors, antibodies, oligonucleotides, lipid-A analogs, microRNAs, and new emerging nano-inhibitors Gao et al. They are synthetic or naturally derived chemical weak bases that can inhibit TLR signaling by accumulation in the acidic intracellular compartments like endosomes and lysosomes leading to suppression of auto antigen presentation, blockade of endosomal TLR7, 8, and 9 signaling, and decrease in cytokine production Kuznik et al.

While HCQ has been found to ameliorate hypertension and aortic endothelial dysfunction Gomez-Guzman et al. They are designed to block the binding of ligands to the specific TLRs. Blockade of TLR2 and 4 signaling by antagonistic antibodies decreases disease severity in sepsis models of Gram-positive and Gram-negative bacteria Daubeuf et al. It could successfully block cytokine release ex vivo and in vivo, prevent LPS-induced flu-like symptoms Monnet et al.

Accordingly, many of them have been developed particularly to treat inflammatory diseases associated with endosomal TLR activation, such as SLE Barrat et al. Recently, it was revealed that targeting of TLR7 and 9 signaling could be a novel strategy for treating the chronic inflammatory process associated with myasthenia gravis, an autoimmune neuromuscular disease Cavalcante et al. Varied forms of IMO, an immune modulatory oligonucleotide, could significantly reduce the expression of inflammatory genes in a mouse model of ILinduced psoriasis Suarez-Farinas et al.

They are small, endogenous non-coding RNAs with post-transcriptional regulatory functions to fine-tune gene expression Bartel, Gold nanoparticles GNPs have caught much attention in nanomedicine Pedrosa et al. All researches done till now, in Egypt, have focused on the implications of TLRs in several diseases.

It was demonstrated that the genetic polymorphisms of TLR2 and TLR4 were not associated with asthma and allergic rhinitis, but significant association was found between these genetic variants and the disease severity in children Hussein et al.

There was no significant association between TLR4 polymorphism and colorectal cancer CRC , but higher serum level of it was associated with a diagnostic prospect in CRC patients Bassuny, TLR4 levels were higher in T2DM patients and found to correlate well with the severity of albuminuria suggesting its possible role in the pathogenesis of diabetic nephropathy Fathy et al.

Increased TLR4 expression on T cells which associated with increased reactive oxygen species ROS generation has been shown to play pathogenic role in autistic children Nadeem et al. Based on the existing scientific literature, it is concluded that TLRs are the main elements in the innate orchestration of immune system. Working in TLRs area including their characterization, expression, ligands recognition, signaling, and implication in many diseases has significantly progressed in past years.

Our main concern should be focused on maintaining TLRs functioning and keeping the integrity of innate immune system. J Inflamm Ahmed S, Moawad M, Elhefny R, Abdullatif M Is toll like receptor 4 a common pathway hypothesis for development of lung cancer and idiopathic pulmonary fibrosis?

Egypt J Chest Dis Tuberc 65 1 — Article Google Scholar. Akira S, Takeda K Toll-like receptor signaling. Nat Rev Immunol — Cell — Int Biol Biomed J Summer 1 3 — Google Scholar. Circ Cardiovasc Interv — Annu Rev Immunol — J Control Release — Drug Metab Toxicol — J Exp Med — Bassuny YMN. Cairo: Cairo University; faculty of pharmacy. Blanco E, Shen H, Ferrari M Principles of nanoparticle design for overcoming biological barriers to drug delivery.

Nat Biotechnol — Immunity 32 3 — Nat Immunol — Mem Inst Oswaldo Cruz. Bresnahan KA, Tanumihardjo SA Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators.

Signaling of Toll-like receptors and innate immunity Mol Immunol — Ann N Y Acad Sci 1 — Mediators Inflamm Nature Immunol — Neurosci Lett —