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Abstract

The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-kappaB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.

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Toll-like receptors: critical proteins linking innate and acquired immunity.

S Akira, K Takeda, T Kaisho (2001)

Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

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Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

Sandra S. Diebold, Tsuneyasu Kaisho, Hiroaki Hemmi … (2004)

Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.

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Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

Osamu Takeuchi, Katsuaki Hoshino, Taro Kawai … (1999)

Toll-like receptor (TLR) 2 and TLR4 are implicated in the recognition of various bacterial cell wall components, such as lipopolysaccharide (LPS). To investigate in vivo roles of TLR2, we generated TLR2-deficient mice. In contrast to LPS unresponsiveness in TLR4-deficient mice, TLR2-deficient mice responded to LPS to the same extent as wild-type mice. TLR2-deficient macrophages were hyporesponsive to several Gram-positive bacterial cell walls as well as Staphylococcus aureus peptidoglycan. TLR4-deficient macrophages lacked the response to Gram-positive lipoteichoic acids. These results demonstrate that TLR2 and TLR4 recognize different bacterial cell wall components in vivo and TLR2 plays a major role in Gram-positive bacterial recognition.

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PubMed ID:: 16410796

DOI:: 10.1038/sj.cdd.4401850

ScienceOpen disciplines: Chemistry

Keywords: Adaptor Proteins, Signal Transducing,metabolism,Adaptor Proteins, Vesicular Transport,Animals,DEAD-box RNA Helicases,Drosophila,Gene Expression Regulation,Humans,Immunity, Innate,Interferon Regulatory Factors,Membrane Proteins,Mice,Models, Biological,Myeloid Differentiation Factor 88,NF-kappa B,Nerve Tissue Proteins,RNA Helicases,Signal Transduction,Toll-Like Receptors,Transcription Factor AP-1

TLR signaling.

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Neuronal Signaling

Most cited references 48

Toll-like receptors: critical proteins linking innate and acquired immunity.

Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

Differential Roles of TLR2 and TLR4 in Recognition of Gram-Negative and Gram-Positive Bacterial Cell Wall Components

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