Limits...
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.

Show MeSH

Related in: MedlinePlus

TLR signalling pathways: TLRs signal through myeloid differentiation primary response gene 88 (MyD88) or/and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways. TLRs 1, 2, 5, 7, 9 require the adaptor MyD88 for their action, whereas TLR3 signals through TRIF-dependent pathway. TLR4 on the other hand activates both MyD88 and TRIF dependent pathways and may induce pro-inflammatory cytokines as well as IFNβ. MyD88 recruits TNF receptor associated factor-6 (TRAF6) and members of the interleukin-1 receptor-associated kinase (IRAK) family, which in turn causes phosphorylation of IκB, after proteasomal degradation of which NFκB dimers are translocated into the nucleus where they cause induction of proinflammatory cytokines. TRIF recruits TRAF3, which through its interaction with serine/threonine-protein kinase 1 (TBK1) and IKKi causes phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates into the nucleus where it causes induction of interferon β (IFNβ). TIRAP, TIR domain-containing adaptor protein; NEMO, NF-kappa-B essential modulator.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3928694&req=5

Figure 2: TLR signalling pathways: TLRs signal through myeloid differentiation primary response gene 88 (MyD88) or/and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways. TLRs 1, 2, 5, 7, 9 require the adaptor MyD88 for their action, whereas TLR3 signals through TRIF-dependent pathway. TLR4 on the other hand activates both MyD88 and TRIF dependent pathways and may induce pro-inflammatory cytokines as well as IFNβ. MyD88 recruits TNF receptor associated factor-6 (TRAF6) and members of the interleukin-1 receptor-associated kinase (IRAK) family, which in turn causes phosphorylation of IκB, after proteasomal degradation of which NFκB dimers are translocated into the nucleus where they cause induction of proinflammatory cytokines. TRIF recruits TRAF3, which through its interaction with serine/threonine-protein kinase 1 (TBK1) and IKKi causes phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates into the nucleus where it causes induction of interferon β (IFNβ). TIRAP, TIR domain-containing adaptor protein; NEMO, NF-kappa-B essential modulator.

Mentions: Most of the inflammatory responses downstream of TLRs are dependent on a common signaling pathway mediated by the adaptor molecule MyD88. On stimulation, MyD88 associates with TIRAP to form a complex which recruits several isoforms of IL-1R-associated kinase (IRAK), IRAK4 being particularly important as it is indispensable for the responses to several TLR ligands. Activated IRAK subsequently associates with tumour-necrosis factor receptor-associated factor (TRAF)-6 leading to the activation of c-Jun N-terminal protein kinase (JNK) - and NFκB- dependent pathways, which in turn regulate the expression of several genes involved in orchestrating the inflammatory response. Alternatively, TLR3 and TLR4 can recruit TRIF to activate IFN responses, where MyD88 requirement is not observed. Recruitment of TRAM/TRIF is known to be critical for type I interferon production and the maturation of dendritic cells, while MyD88 is essential for the production of Th1 supporting inflammatory responses (Fig. 2). Depending upon the ligands in question, different TLRs induce distinct patterns of cytokine responses resulting in a Th1/Th2 polarization that is most suitable for the pathogen. For instance, while activation of TLR4 in dendritic cells (DCs) induces production of IL-12, thereby skewing Th differentiation towards the Th1 type, indirect activation of DCs by inflammatory mediators alone does not promote Th cell differentiation in spite of T-cell clonal proliferation53. Hence, individual TLRs are important in both triggering and modulating the activation of the adaptive immune response54.


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)

TLR signalling pathways: TLRs signal through myeloid differentiation primary response gene 88 (MyD88) or/and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways. TLRs 1, 2, 5, 7, 9 require the adaptor MyD88 for their action, whereas TLR3 signals through TRIF-dependent pathway. TLR4 on the other hand activates both MyD88 and TRIF dependent pathways and may induce pro-inflammatory cytokines as well as IFNβ. MyD88 recruits TNF receptor associated factor-6 (TRAF6) and members of the interleukin-1 receptor-associated kinase (IRAK) family, which in turn causes phosphorylation of IκB, after proteasomal degradation of which NFκB dimers are translocated into the nucleus where they cause induction of proinflammatory cytokines. TRIF recruits TRAF3, which through its interaction with serine/threonine-protein kinase 1 (TBK1) and IKKi causes phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates into the nucleus where it causes induction of interferon β (IFNβ). TIRAP, TIR domain-containing adaptor protein; NEMO, NF-kappa-B essential modulator.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: TLR signalling pathways: TLRs signal through myeloid differentiation primary response gene 88 (MyD88) or/and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways. TLRs 1, 2, 5, 7, 9 require the adaptor MyD88 for their action, whereas TLR3 signals through TRIF-dependent pathway. TLR4 on the other hand activates both MyD88 and TRIF dependent pathways and may induce pro-inflammatory cytokines as well as IFNβ. MyD88 recruits TNF receptor associated factor-6 (TRAF6) and members of the interleukin-1 receptor-associated kinase (IRAK) family, which in turn causes phosphorylation of IκB, after proteasomal degradation of which NFκB dimers are translocated into the nucleus where they cause induction of proinflammatory cytokines. TRIF recruits TRAF3, which through its interaction with serine/threonine-protein kinase 1 (TBK1) and IKKi causes phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates into the nucleus where it causes induction of interferon β (IFNβ). TIRAP, TIR domain-containing adaptor protein; NEMO, NF-kappa-B essential modulator.
Mentions: Most of the inflammatory responses downstream of TLRs are dependent on a common signaling pathway mediated by the adaptor molecule MyD88. On stimulation, MyD88 associates with TIRAP to form a complex which recruits several isoforms of IL-1R-associated kinase (IRAK), IRAK4 being particularly important as it is indispensable for the responses to several TLR ligands. Activated IRAK subsequently associates with tumour-necrosis factor receptor-associated factor (TRAF)-6 leading to the activation of c-Jun N-terminal protein kinase (JNK) - and NFκB- dependent pathways, which in turn regulate the expression of several genes involved in orchestrating the inflammatory response. Alternatively, TLR3 and TLR4 can recruit TRIF to activate IFN responses, where MyD88 requirement is not observed. Recruitment of TRAM/TRIF is known to be critical for type I interferon production and the maturation of dendritic cells, while MyD88 is essential for the production of Th1 supporting inflammatory responses (Fig. 2). Depending upon the ligands in question, different TLRs induce distinct patterns of cytokine responses resulting in a Th1/Th2 polarization that is most suitable for the pathogen. For instance, while activation of TLR4 in dendritic cells (DCs) induces production of IL-12, thereby skewing Th differentiation towards the Th1 type, indirect activation of DCs by inflammatory mediators alone does not promote Th cell differentiation in spite of T-cell clonal proliferation53. Hence, individual TLRs are important in both triggering and modulating the activation of the adaptive immune response54.

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