Evaluating the role of Toll-like receptors in diseases of the central nervous system |
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Authors: | Carty Michael Bowie Andrew G |
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Affiliation: | School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland |
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Abstract: | A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses and are also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain. |
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Keywords: | Abbreviations: AD, Alzheimer's disease ALRs, Aim2 like receptors Aβ, Amyloidβ BBB, blood brain barrier CARD, caspase activating and recruitment domain CB, Cerebral malaria CFA, complete freunds adjuvant CNS, central nervous system CpG, cytosine phosphate guanosine DAMPs, danger associates molecular patterns DCs, dendritic cells dsRNA, double-stranded RNA EAE, experimental autoimmune encephalitis EGF, epidermal growth factor ERK, extracellular signal-regulated kinase FADD, Fas-associated death domain FAβ, fibrillar Aβ FPRL1, formyl peptide receptor-like 1 GBS, group B streptococcus GPI, Glycosylphosphatidylinositol HMGB1, high mobility group box 1 protein HSE, Herpes simplex virus induced encephalitis HSP, heat shock proteins HSV, Herpes simplex virus IL-1β, Interleukin-1β IL-6, Interleukin-6 iNOS, inducible nitric oxide synthase IRAK, IL-1 receptor&ndash associated kinases IRF, Interferon Regulatory Factor JNK, c-Jun N-terminal kinase KO, knockout LPS, lipopolysaccharide Mal, MyD88 adaptor-like protein MAPK, Mitogen-activated protein kinase MMPs, matrix metalloproteinases MS, multiple sclerosis MyD88, Myeloid differentiation factor 88 NACHT, domain present in NAIP, CIITA, HET-E, TP-1 NAP1, NAK-associated protein 1 NFκB, Nuclear factor κB NLRs, Nod-like Receptors NO, nitric oxide NPCs, neural progenitor cells PAMP, pathogen-associated molecular pattern polyI:C, polyinosine-deoxycytidylic acid PRRs, pattern recognition receptors RIP1, receptor interacting protein 1 RLRs, Rig like receptors RLRs ROS, reactive oxygen species SARM, sterile α-and armadillo-motif containing protein SINTBAD, similar to NAP1 TBK1 adaptor TAK1, transforming growth factor-b-activated protein kinase 1 TANK, TRAF family member-associated NFκB activator TBK1, TANK-binding kinase TIR, Toll/IL-1 receptor TLR, Toll-like receptor TNFα, tumour necrosis factor α TRADD, TNF-R-associated death domain TRAF6, tumor necrosis factor receptor associated factor 6 TRAM, TRIF-related adaptor protein TRIF, TIR domain-containing adaptor VEGF, vascular endothelial growth factor WT, wild type |
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