Novel therapeutic strategies based on toll-like receptor signaling (original) (raw)
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Toll-like receptors. II. Distribution and pathways involved in TLR signalling
Folia biologica, 2005
The innate immune system senses invading microorganisms by a phylogenetically conserved family of proteins--TLRs. They are expressed in several types of cells that represent a route of entry of pathogens into the host organism and that can contribute to protection against infection. Except for cells of the immune system, TLRs are present in epithelial cells of the skin, respiratory, intestinal, and genitourinary tracts that form the first protective barrier to invading pathogens. Polarized regulation of TLR expression in epithelial cells explains why pathogenic but not commensal bacteria elicit inflammatory responses. TLR-induced intracellular signalling pathways show remarkable complexity: apart from a common signalling pathway, additional signalling pathways specific for each of the TLRs are responsible for a fine tuning of the immune response, thus securing effective pathogen-directed biological responses.
Toll is a Drosophila gene essential for ontogenesis and antimicrobial resistance. Several hortologues of Toll have been identified and cloned in vertebrates, namely Toll-like receptors (TLR). Human TLR are a growing family of molecules involved in innate immunity. TLR are structurally characterized by a cytoplasmic Toll/interleukin-1R (TIR) domain and by extracellular leucine-rich repeats. TLR characterized so far activate the MyD88/IRAK signaling cascade, which bifurcates and leads to NF-B and c-Jun/ATF2/TCF activation. Genetic, gene transfer, and dominant-negative approaches have involved TLR family members (TLR2 and TLR4) in lipopolysaccharide recognition and signaling. Accumulating evidence suggests that some TLR molecules are also involved in signaling receptor complexes that recognize components of gram-positive bacteria and mycobacteria. However, the definitive role of other TLR is still lacking. A systematic approach has been used to determine whether different human leukocyte populations selectively or specifically expressed TLR mRNA. Based on expression pattern, TLR can be classified as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5), and specific (TLR3). Expression and regulation of distinct though overlapping ligand recognition patterns may underlie the existence of a numerous, seemingly redundant, TLR family. Alternately, the expression of a TLR in a single cell type may indicate a specific role for this molecule in a restricted setting. J. Leukoc. Biol. 67: 450-456; 2000.
Toll-like Receptors are Key Participants in Innate Immune Responses
Biological Research, 2007
During an infection, one of the principal challenges for the host is to detect the pathogen and activate a rapid defensive response. The Toll-like family of receptors (TLRs), among other pattern recognition receptors (PRR), performs this detection process in vertebrate and invertebrate organisms. These type I transmembrane receptors identify microbial conserved structures or pathogen-associated molecular patterns (PAMPs). Recognition of microbial components by TLRs initiates signaling transduction pathways that induce gene expression. These gene products regulate innate immune responses and further develop an antigen-specific acquired immunity. TLR signaling pathways are regulated by intracellular adaptor molecules, such as MyD88, TIRAP/Mal, between others that provide specificity of individual TLR-mediated signaling pathways. TLRmediated activation of innate immunity is involved not only in host defense against pathogens but also in immune disorders. The involvement of TLR-mediated pathways in auto-immune and inflammatory diseases is described in this review article.
Important aspects of Toll-like receptors, ligands and their signaling pathways
Inflammation Research, 2010
Due to the rapid increase of new information on the multiple roles of Toll-like receptors (TLRs), this paper reviews several main properties of TLRs and their ligands and signaling pathways. The investigation of pathogen infections in knockout mice suggests that specific TLRs play a key role in the activation of immune responses. Although the investigation of TLR biology is just beginning, a number of important findings are emerging. This review focuses on the following seven aspects of this emerging field: (a) a history of TLR and ligand studies; (b) the molecular basis of recognition by TLRs: TLR structures, pathogen-associated molecular pattern binding sites, TLR locations and functional responses; (c) cell types in TLR expression; (d) an overview of TLRs and their ligands: expression and ligands of cell-surface TLRs and of intracellular TLRs; (e) TLR-signaling pathways; (f) discussion: TLRs control of innate and adaptive systems; the trafficking of intracellular TLRs to endolysosomes; investigation of TLRs in regulating microRNA; investigation of crystal structure of TLRs with ligand binding; incidence of infectious diseases associated with single nucleotide polymorphisms (SNPs) in TLR genes; risk of cancer related to SNPs in TLR genes; TLR-ligand mediated anti-cancer effects; and TLR-ligand induced chronic inflammation and tumorigenesis; and (g) conclusions.
The Toll-Like Receptors Signaling Network
The toll-like receptors (TLRs) family of transmembrane proteins is an integrated part of the innate immune system. These receptors are involved in the recognition of the pathogens, the activation of innate, inflammatory mechanisms to control pathogens' spread, and the subsequent activation of the adaptive immune responses directed to the elimination of the pathogens. A subset of TLRs recognizes viral components and induces antiviral responses. This summarizing report presents data demonstrating that TLRs are a type of pattern recognition receptors and act as "sentinels" of the immune innate system, sensing a large array of microbial ligands. The toll-like receptors are included in the large group of recognition molecules known as Pattern Recognition Receptors (PRRs). Other molecular structures are components of this network, such as secreted molecules that circulate in blood and lymph, surface receptors on phagocytic cells (macrophages, monocytes) that bind the pathoge...
Toll-like receptor signalling and the clinical benefits that lie within
Inflammation Research, 2007
TLRs are of crucial importance to the innate immune system by recognising molecules that are broadly shared by pathogens but distinguishable from host molecules. The innate immune system works to defend the body from microbial infection by initiating infl ammation, the extreme form of which is sepsis. The discovery that endogenous ligands, as well as microbial components, are recognised by TLRs, raise the possibility of these receptors and their associated adaper molecules, as potential targets for the development of agonists and antogonists for the treatment of various pathological diseases, and their manipulation as potential adjuvants in vaccine development. By elucidating the mechanisms of TLR signalling pathways involving adapter molecules like MyD88, Mal, TRIF and TRAM combined with the identifi cation of single nucleotide polymorphisms (SNPs) within these receptors and the unique genes that are expressed upon recognition, will assit in the development of therapeutics to alleviate the consequences of microbial-mediated infl ammation, which include infl ammatory disorders and septic shock.
Toll‐like Receptors (TLRs) are identified as pattern recognition receptors (PRRs) present in vertebrates and invertebrates which recognize the pathogen‐ associated molecular patterns (PAMPs) shared by pathogens. They are a type of innate immune receptors, involved in the cytokine production, cellular activation and phagocytosis of microorganisms during microbial infection. They exist on various immune cells therefore, considered for targeted immunotherapeutic research in current approaches. In the present review, we have extensively discussed that how TLRs play a crucial role in mediating the innate immune response and forming a bridge between innate and adaptive immunity. Moreover, their role in immunological disorders and treatment of human diseases is also discussed in length.