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Toll-Like Receptors As Potential Therapeutic Targets for Multiple Diseases

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Toll-Like Receptors As Potential Therapeutic Targets for Multiple Diseases REVIEWS TOLL-LIKE RECEPTORS AS POTENTIAL THERAPEUTIC TARGETS FOR MULTIPLE DISEASES Claudia Zuany-Amorim, John Hastewell and Christoph Walker The family of Toll-like receptors (TLRs) is receiving considerable attention as potential regulators and controllers of the immune response through their ability to recognize pathogen-associated molecular patterns. The discovery that endogenous ligands, as well as microbial components, are recognized by TLRs, and that small-molecular-mass synthetic compounds activate TLRs, raised interest in these receptors as potential targets for the development of new therapies for multiple diseases. In this review, we discuss the current and future use of TLR agonists or antagonists in chronic inflammatory diseases and highlight potential problems that are associated with such approaches. 2 INNATE IMMUNITY The immune system has been divided traditionally into PAMPs . The first report of a mammalian TLR and its The early response of a host to an INNATE and ADAPTIVE component, each of which has involvement in host defence — TLR-4 as a receptor for infections by pathogens, such as different roles and functions in defending the organism LIPOPOLYSACCHARIDE (LPS)3 — was followed rapidly by the bacteria and viruses, before the against foreign agents, such as bacteria or viruses. The discovery that the human genome contains several antigen-specific, adaptive innate immune system has developed a series of con- TLRs — ten have been found so far, TLR-1–TLR-10. immune response is induced. served receptors, known as pattern-recognition recep- Members of the TLR family share characteristic extra- ADAPTIVE IMMUNITY tors (PRRs), that recognize specific pathogen-associated cellular and cytoplasmic domains. Their extracellular Also known as acquired molecular patterns (PAMPs), thereby allowing the innate domains include several leucine-rich repeats (LRRs), immunity. Host defence that is immune system to distinguish self-molecules from whereas the cytoplasmic domain is similar to the cyto- mediated by B and T cells after exposure to antigen and which pathogen-associated non-self structures and initiate plasmic portion of the interleukin-1 receptor (IL-1R), 1 shows specificity, memory and the host defence response . Recognition of PAMPs by which is commonly known as the Toll/IL-1R homolo- self/non-self recognition. PRRs results in the activation of signalling events that gous region (TIR domain)4. Consistent with their func- induce the expression of effector molecules, such as tion as PRRs, TLRs are expressed mainly in the cell cytokines, chemokines and co-stimulatory molecules, types that are involved in the first line of defence, such which subsequently control the activation of an antigen- as DENDRITIC CELLS, MACROPHAGES, NEUTROPHILS, mucosal specific adaptive immune response. An important epithelial cells and dermal endothelial cells5. Distinct advance in our understanding of early events in micro- subsets of dendritic cells and dendritic-cell precursors bial recognition and the subsequent development of express different subsets of TLRs that enable them to Novartis Horsham immune responses has been the identification of Toll- induce specific patterns of immune response to differ- Research Centre, Novartis Pharmaceutical like receptors (TLRs) as key PRRs of the innate ent pathogens. For example, plasmacytoid dendritic Ltd, Wimblehurst Road, immune system1. cells strongly express TLR-9, whereas myeloid dendritic Horsham, West Sussex The gene that encodes the Toll protein was shown to cells do not. Instead, they express other TLRs, including RH12 5AB, UK. be involved in embryonic development in Drosophila, TLR-4, which cause them to be activated by a different Correspondence to C.W. and was identified subsequently as being an essential set of PAMPs, including LPS6. Activation of dendritic e-mail: christoph.walker@ pharma.novartis.com molecule for driving the immune response. TLRs are cells by stimulation of TLRs results in the production of doi:10.1038/nrd914 mammalian homologues of this protein that can detect cytokines, such as IL-12, that induce T-helper type 1 NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | OCTOBER 2002 | 797 © 2002 Nature Publishing Group REVIEWS Table 1 | TLR-family members and exogenous and endogenous ligands TLR-family member Exogenous ligands Endogenous ligands TLR-1 (can associate with TLR-2) Mycobacterial lipoprotein, triacylated Unknown lipopeptides TLR-2 LPS, yeast-particle zymosan, peptidoglycan HSP60, surfactant protein-A (can associate with TLR-1 or TLR-6) (bacteria), lipoproteins (bacteria and mycoplasmas), GPI anchor from Trypanosoma cruzi TLR-3 Poly(I:C) (viral dsRNA) Unknown TLR-4 LPS, respiratory syncytial virus HSP60, HSP70, saturated LIPOPOLYSACCHARIDE fatty acids, unsaturated fatty (LPS). A lipopolysaccharide acids, hyaluronic-acid comprises three regions: fragment, surfactant protein-A a branched core oligosaccharide, TLR-5 Flagellin Unknown linked to a lipid component and an O-linked oligosaccharide. TLR-6 (can associate with TLR-2) Mycoplasma lipoproteins, lipoteichoic acid, Unknown The exact composition differs peptidoglycan (bacteria) between Gram-negative TLR-7 Unknown; synthetic compounds, such Unknown bacteria. LPS induces an acute as resiquimod or imiquimod, activate inflammatory reaction both the receptor in vitro and in vivo. TLR-8 Unknown; synthetic compounds, such as Unknown resiquimod or imiquimod, activate the DENDRITIC CELL receptor A bone-marrow-derived leukocyte that is specialized TLR-9 CpG DNA dsDNA for the uptake, transport, TLR-10 Unknown Unknown processing and presentation CpG, cytosine–guanine repeat; ds, double stranded; GPI, glycosyl phosphatidylinositol; HSP, heat-shock protein; LPS, lipopolysaccharide; of antigens to T cells. Poly(I:C), poly(inosine: cytidylic) acid; TLR, Toll-like receptor. MACROPHAGE A large, myeloid cell derived (T 1) CELLS from a monocyte in the H , which tends to direct the adaptive immune Tlr-2-deficient mice have a normal inflammatory 6 circulation that functions in response to differentiate towards a TH1 phenotype .The response to LPS, but macrophages from these animals phagocytosis, antigen processing identification of TLRs as PRRs that are involved in con- are less responsive to Gram-positive bacterial cell walls and presentation, secretion of trolling dendritic-cell activation led to substantial interest and PEPTIDOGLYCAN. Indeed, TLR-2 recognizes LPS from cytokines and antibody- in these receptors as possible regulators of adaptive Porphyromonas gingivitis9 and Leptospira interrogans10, dependent, cell-mediated cytotoxicity. immune responses and, by inducing a specific cytokine which differs in structure from the LPS of Gram-negative environment, their involvement in the pathogenesis of bacteria. These results are evidence of TLR selectivity in NEUTROPHIL several chronic inflammatory diseases. Therefore, we PAMP recognition, although other TLRs can recognize A circulating granulocyte that focus our discussion on the emerging role of TLRs in the the same components of both Gram-negative and can phagocytose pathogens, such as bacteria, and release pathogenesis of inflammatory diseases and how agonists Gram-positive bacteria. Indeed, flagellin, the principal proteolytic enzymes. or antagonists of these receptors might be used to treat element of bacteria flagella, is a highly virulent molecule various pathological conditions. We describe the basic that is recognized by TLR-5 (REF.11), whereas TLR-9 is T 1 CELL H mechanism of an allergic inflammatory response as an required for the inflammatory response that is triggered A terminally differentiated example to show how targeting TLRs might offer promis- by hypomethylated bacterial DNA12. TLRs also trigger subclass of T-helper cell that secretes a restricted repertoire ing new therapeutic benefits. In addition, the current and an innate immune response to viruses that produce of cytokines, including IL-2 future use of TLR agonists and antagonists in other double-stranded RNA, and a reduced response to the and IFN-γ. chronic inflammatory diseases, and the activation of dsRNA analogue polyinosine–polycytidylic acid was TLRs by exogenous or endogenous ligands are discussed. observed in Tlr-3-deficient mice13. Recently, Takeuchi GRAM-NEGATIVE BACTERIA 14 Bacteria that do not retain a et al. showed that TLR-1 is involved in the recognition basic blue dye during the Gram TLRs: members and ligands of mycobacterial lipoprotein and triacylated lipopetides. stain procedure. Their cell walls Several reviews describe elegantly the known members In addition, TLRs can form multimeric complexes are thin, consisting of a layer of of the TLR family, their ligands and the signalling path- (homodimers or heterodimers) to increase the spec- lipopolysaccharide outside of ways that are induced by stimulation of the receptors4–6. trum of molecules that they recognize. For example, the a peptidoglycan layer. Therefore, we summarize only briefly the current know- cytoplasmic domain of TLR-2 can form functional pairs GRAM-POSITIVE BACTERIA ledge, focusing on the most important information that with TLR-6 and TLR-1, leading to signal transduction Bacteria that retain a basic blue is required to understand the function of TLRs (TABLE 1). and cytokine expression after ligand activation4. dye during the Gram-stain Different TLRs have been shown to be crucial for the procedure. Their cell wall is thicker than that of Gram- selective recognition of specific PAMPs that are common TLR signal transduction negative
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