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Targeting toll-like receptor signaling as a novel approach to prevent ocular infectious diseases.

Pandey RK, Yu FS, Kumar A - Indian J. Med. Res. (2013)

Bottom Line: Toll-like receptors (TLRs) play a key role in the innate immune response to invading pathogens.In the last several years, extensive research efforts have provided a considerable wealth of information on the expression and function of TLRs in the eye, with significant implications for better understanding of pathogenesis of infectious eye diseases affecting the cornea, uvea, and the retina.In this review, by using bacterial keratitis and endophthalmitis as examples, we discuss the possibilities of targeting TLR signaling for the prevention or treatment of ocular infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Kresge Eye Institute; Department of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.

ABSTRACT
Toll-like receptors (TLRs) play a key role in the innate immune response to invading pathogens. Thus, their discovery has opened up a wide range of therapeutic possibilities for various infectious and inflammatory diseases. In the last several years, extensive research efforts have provided a considerable wealth of information on the expression and function of TLRs in the eye, with significant implications for better understanding of pathogenesis of infectious eye diseases affecting the cornea, uvea, and the retina. In this review, by using bacterial keratitis and endophthalmitis as examples, we discuss the possibilities of targeting TLR signaling for the prevention or treatment of ocular infectious diseases.

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Cellular distribution of Toll-like receptors (TLRs): TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface, while TLRs 3, 7, 8 and 9 are expressed intracellularly on endosomal membranes. After binding to their respective ligands, TLRs 3, 4, 5, 7 and 9 are thought to signal through their homodimers; TLR2 may heterodimerize with TLR1 or TLR6 depending upon the ligand in question. TLR4 requires MD2 in addition to its ligand for signal transduction. HSP70, heat shock protein 70; HCV core, hepatitis C virus; LTA, lipoteichoic acid.
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Figure 1: Cellular distribution of Toll-like receptors (TLRs): TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface, while TLRs 3, 7, 8 and 9 are expressed intracellularly on endosomal membranes. After binding to their respective ligands, TLRs 3, 4, 5, 7 and 9 are thought to signal through their homodimers; TLR2 may heterodimerize with TLR1 or TLR6 depending upon the ligand in question. TLR4 requires MD2 in addition to its ligand for signal transduction. HSP70, heat shock protein 70; HCV core, hepatitis C virus; LTA, lipoteichoic acid.

Mentions: TLRs are type I transmembrane glycoprotein receptors which comprise an extracellular domain containing 19-25 tandem repeats of leucine-rich motifs, a transmembrane domain and a conserved cytoplasmic domain of around 200 amino acids that is referred to as the Toll/IL-1 receptor (TIR) domain due to its homology to the signaling domain of the interleukin (IL)-1 receptor37. The cytoplasmic domain mediates activation of intracellular signaling pathways by ligating to the TIR-containing adaptor proteins: MyD88, TIR domain-containing adaptor protein (TIRAP)-also known as MyD88-adaptor-like (MAL), TIR domain-containing adaptor protein inducing IFNβ (TRIF) and TRIF-related adaptor molecule (TRAM)3839. Once activated, TLRs signal through different intracellular signaling cascades, generally resulting in the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) in MyD88-dependent pathways and/or type I interferons (IFNs) in TRIF-dependent antiviral pathways, leading to the induction of cytokines, chemokines and cell adhesion molecules40. To date, 13 mammalian TLRs have been identified, of which 10 functional TLRs are known to be expressed in humans and 12 functional TLRs in mice with TLRs1-9 being conserved in both. TLR10 and TLRs11-13 are unique to humans and mice, respectively. TLR1, 2, 4, 5, 6, and 10 are typically displayed on the cell surface, where these interact with their corresponding ligands. TLR3, 7, 8, and 9 are typically located intracellularly on endosomal membranes as their natural ligands might only be found in the acidic compartments of the cell41. TLRs associate with other proteins to form a heteromeric receptor complex (Fig. 1). These accessory proteins might be one of the TLRs that form either homo- or heterodimeric complexes or proteins which do not belong to the TLR family. This dimerization induces conformational changes which are essential for the recruitment of adaptor molecules to the cytosolic domain of TLRs. TLR2 forms heterodimers with TLR6 and with TLR1 and is a sentinel for the recognition of Gram-negative bacteria through diacyl and triacyl lipopeptides, respectively4243. TLR4 forms a complex with lipopolysaccharide (LPS) binding protein (LBP), MD-2 and CD14 and recognizes LPS from Gram-negative bacteria4445. TLR5 recognizes flagellin, a component of bacterial flagella46. The ligand for TLR10 is yet to be discovered, though it is known to dimerize with TLR1 and TLR247. TLR3 recognizes double stranded RNA from viruses48 whereas TLR7 and 8 recognize viral single stranded RNA4950. TLR9 spots the presence of unmethylated cytosine-phosphateguanosine dinucleotide (CpG) motifs of both bacterial and viral DNA5152.


Targeting toll-like receptor signaling as a novel approach to prevent ocular infectious diseases.

Pandey RK, Yu FS, Kumar A - Indian J. Med. Res. (2013)

Cellular distribution of Toll-like receptors (TLRs): TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface, while TLRs 3, 7, 8 and 9 are expressed intracellularly on endosomal membranes. After binding to their respective ligands, TLRs 3, 4, 5, 7 and 9 are thought to signal through their homodimers; TLR2 may heterodimerize with TLR1 or TLR6 depending upon the ligand in question. TLR4 requires MD2 in addition to its ligand for signal transduction. HSP70, heat shock protein 70; HCV core, hepatitis C virus; LTA, lipoteichoic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3928694&req=5

Figure 1: Cellular distribution of Toll-like receptors (TLRs): TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface, while TLRs 3, 7, 8 and 9 are expressed intracellularly on endosomal membranes. After binding to their respective ligands, TLRs 3, 4, 5, 7 and 9 are thought to signal through their homodimers; TLR2 may heterodimerize with TLR1 or TLR6 depending upon the ligand in question. TLR4 requires MD2 in addition to its ligand for signal transduction. HSP70, heat shock protein 70; HCV core, hepatitis C virus; LTA, lipoteichoic acid.
Mentions: TLRs are type I transmembrane glycoprotein receptors which comprise an extracellular domain containing 19-25 tandem repeats of leucine-rich motifs, a transmembrane domain and a conserved cytoplasmic domain of around 200 amino acids that is referred to as the Toll/IL-1 receptor (TIR) domain due to its homology to the signaling domain of the interleukin (IL)-1 receptor37. The cytoplasmic domain mediates activation of intracellular signaling pathways by ligating to the TIR-containing adaptor proteins: MyD88, TIR domain-containing adaptor protein (TIRAP)-also known as MyD88-adaptor-like (MAL), TIR domain-containing adaptor protein inducing IFNβ (TRIF) and TRIF-related adaptor molecule (TRAM)3839. Once activated, TLRs signal through different intracellular signaling cascades, generally resulting in the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) in MyD88-dependent pathways and/or type I interferons (IFNs) in TRIF-dependent antiviral pathways, leading to the induction of cytokines, chemokines and cell adhesion molecules40. To date, 13 mammalian TLRs have been identified, of which 10 functional TLRs are known to be expressed in humans and 12 functional TLRs in mice with TLRs1-9 being conserved in both. TLR10 and TLRs11-13 are unique to humans and mice, respectively. TLR1, 2, 4, 5, 6, and 10 are typically displayed on the cell surface, where these interact with their corresponding ligands. TLR3, 7, 8, and 9 are typically located intracellularly on endosomal membranes as their natural ligands might only be found in the acidic compartments of the cell41. TLRs associate with other proteins to form a heteromeric receptor complex (Fig. 1). These accessory proteins might be one of the TLRs that form either homo- or heterodimeric complexes or proteins which do not belong to the TLR family. This dimerization induces conformational changes which are essential for the recruitment of adaptor molecules to the cytosolic domain of TLRs. TLR2 forms heterodimers with TLR6 and with TLR1 and is a sentinel for the recognition of Gram-negative bacteria through diacyl and triacyl lipopeptides, respectively4243. TLR4 forms a complex with lipopolysaccharide (LPS) binding protein (LBP), MD-2 and CD14 and recognizes LPS from Gram-negative bacteria4445. TLR5 recognizes flagellin, a component of bacterial flagella46. The ligand for TLR10 is yet to be discovered, though it is known to dimerize with TLR1 and TLR247. TLR3 recognizes double stranded RNA from viruses48 whereas TLR7 and 8 recognize viral single stranded RNA4950. TLR9 spots the presence of unmethylated cytosine-phosphateguanosine dinucleotide (CpG) motifs of both bacterial and viral DNA5152.

Bottom Line: Toll-like receptors (TLRs) play a key role in the innate immune response to invading pathogens.In the last several years, extensive research efforts have provided a considerable wealth of information on the expression and function of TLRs in the eye, with significant implications for better understanding of pathogenesis of infectious eye diseases affecting the cornea, uvea, and the retina.In this review, by using bacterial keratitis and endophthalmitis as examples, we discuss the possibilities of targeting TLR signaling for the prevention or treatment of ocular infectious diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Kresge Eye Institute; Department of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.

ABSTRACT
Toll-like receptors (TLRs) play a key role in the innate immune response to invading pathogens. Thus, their discovery has opened up a wide range of therapeutic possibilities for various infectious and inflammatory diseases. In the last several years, extensive research efforts have provided a considerable wealth of information on the expression and function of TLRs in the eye, with significant implications for better understanding of pathogenesis of infectious eye diseases affecting the cornea, uvea, and the retina. In this review, by using bacterial keratitis and endophthalmitis as examples, we discuss the possibilities of targeting TLR signaling for the prevention or treatment of ocular infectious diseases.

Show MeSH
Related in: MedlinePlus