KEY POINTS * The innate immune system has a series of conserved receptors, known as pattern-recognition receptors, which recognize specific pathogen-associated molecular patterns. The

identification of Toll-like receptors (TLRs) that fulfil this role is an important advance in our understanding of the early events of host defence. Moreover, TLRs are potential regulators

and controllers of an antigen-specific adaptive immune response. * TLRs are type I transmembrane proteins that are evolutionarily conserved between insects and humans. So far, ten TLRs have

been identified. Consistent with their function as pathogen-recognition receptors, TLRs are expressed mainly in the cell types that are involved in the first line of defence. TLRs activate

activate an uncontrolled network of host-derived mediators, as seen in sepsis or pathogen-induced disease exacerbations. * Allergic asthma is chosen as an example of a chronic, T-helper

type 2 (TH2)-cell-driven inflammatory disease to show how TLR agonists or antagonists might offer possibilities for therapeutic intervention. The hygiene hypothesis proposes that the

relatively sterile environment and increased use of antibiotics for childhood infections in Western countries has contributed to the recent epidemic of asthma. So, TLR-activating bacterial

vaccines or selective TLR agonists that mimic host-defence-induced responses might have therapeutic benefit in atopic diseases. * In addition to the development of new therapies for diseases

such as sepsis or disease-modifying therapies that result in immune deviation in asthma, reagents that enhance TLR-signalling pathways can be powerful adjuvants for fighting pathogens or

cancer. * It has been shown that TLRs can be stimulated by endogenous ligands, such as heat-shock proteins, saturated and unsaturated fatty acids, hyaluronic-acid fragments, double-stranded

DNA and surfactant protein-A. These observations and the discovery of low-molecular-mass synthetic compounds that activate TLRs raises interest in these receptors as being potential targets

for the development of new therapies in multiple diseases. ABSTRACT 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.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS INHIBITORY PATTERN RECOGNITION RECEPTORS: LESSONS FROM LAIR1 Article 27 May 2025 IMMUNE-MEDIATED INFLAMMATORY DISEASE THERAPEUTICS: PAST,

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Research Centre, Novartis Pharmaceutical Ltd, Wimblehurst Road, Horsham, RH12 5AB, West Sussex, UK Claudia Zuany-Amorim, John Hastewell & Christoph Walker Authors * Claudia Zuany-Amorim

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DATABASES FLYBASE Toll INTERPRO TIR domain LOCUSLINK CD4 CD14 COX-2 GM-CSF IFN-α IFN-γ IKK IL-1 IL-2 IL-4 IL-5 IL-6 IL-10 IL-12 IL-13 IL-18 IL-1R iNOS IRAK MYD88 NF-κB NOD2 surfactant

protein-A TIRAP TLR-1 TLR-2 TLR-3 TLR-4 TLR-5 TLR-6 TLR-7 TLR-8 TLR-9 TLR-10 TNF TOLLIP TRAF6 OMIM Crohn's disease type 1 diabetes GLOSSARY * INNATE IMMUNITY The early response of a

host to infections by pathogens, such as bacteria and viruses, before the antigen-specific, adaptive immune response is induced. * ADAPTIVE IMMUNITY Also known as acquired immunity. Host

defence that is mediated by B and T cells after exposure to antigen and which shows specificity, memory and self/non-self recognition. * LIPOPOLYSACCHARIDE (LPS). A lipopolysaccharide

comprises three regions: a branched core oligosaccharide, linked to a lipid component and an _O_-linked oligosaccharide. The exact composition differs between Gram-negative bacteria. LPS

induces an acute inflammatory reaction both _in vitro_ and _in vivo_. * DENDRITIC CELL A bone-marrow-derived leukocyte that is specialized for the uptake, transport, processing and

presentation of antigens to T cells. * MACROPHAGE A large, myeloid cell derived from a monocyte in the circulation that functions in phagocytosis, antigen processing and presentation,

secretion of cytokines and antibody-dependent, cell-mediated cytotoxicity. * NEUTROPHIL A circulating granulocyte that can phagocytose pathogens, such as bacteria, and release proteolytic

enzymes. * TH1 CELL A terminally differentiated subclass of T-helper cell that secretes a restricted repertoire of cytokines, including IL-2 and IFN-γ. * GRAM-NEGATIVE BACTERIA Bacteria that

do not retain a basic blue dye during the Gram stain procedure. Their cell walls are thin, consisting of a layer of lipopolysaccharide outside of a peptidoglycan layer. * GRAM-POSITIVE

BACTERIA Bacteria that retain a basic blue dye during the Gram-stain procedure. Their cell wall is thicker than that of Gram-negative bacteria, containing more peptidoglycan. * PEPTIDOGLYCAN

Peptide–saccharide conjugates that are constituents of the bacterial cell wall. * NUCLEAR FACTOR-κB (NF-κB). A transcription factor that is important for pro-inflammatory and anti-apoptotic

responses. * TH2 CELLS A terminally differentiated subclass of T-helper cells that secretes a restricted repertoire of cytokines, including IL-4, IL-5, IL-9 and IL-13. * IMMUNOGLOBULIN E

(Ig)E A subtype of immunoglobulins that is associated with allergy. Elevated levels are the hallmark of the atopic state. Cells that are activated by allergen-specific IgE to release

inflammatory products contribute to allergic diseases, such as asthma, allergic rhinitis and anaphylaxis. * EOSINOPHIL An allergic effector cell (granulocyte) that is strongly associated

with allergic inflammation. Secreted products of eosinophils might contribute to airway obstruction, bronchial hyperresponsiveness and other pathologies in allergic asthma. * MAST CELLS A

type of leukocyte that has large secretory granules that contain histamine and various other preformed protein mediators. Mast cells release these proteins after ligation and crosslinking of

allergen-specific IgE bound to high-affinity IgE receptors that are expressed on these cells. * ATOPY The propensity to develop hypersensitivity reactions, such as asthma, which is strongly

linked to TH2 cells and IgE. * CpG DNA A region of DNA that has patterns of CpG motifs (cytosine–guanine repeats). These motifs can be methylated (on cytosine) — an event that is rare in

bacteria — giving rise to hypermethylated CpG regions. * GLUCOCORTICOSTEROID A natural or synthetic molecule that influences carbohydrate and protein metabolism. An important drug target, as

the mechanism also produces an anti-inflammatory effect. * REGULATORY T CELLS Lymphocytes that can suppress the activity of naive or effector T cells, either by cell–cell contact or by

producing cytokines, such as TGF-β or IL-10. * NOD2 An intracellular protein that contains the leucine-rich repeat (LRR) structural element (similar to TLRs) and can bind lipopolysaccharides

and regulate NF-κB function. * HEAT-SHOCK PROTEINS (HSPS). A ubiquitous group of intracellular proteins that have a range of functions; for example, as chaperones. Many HSPs are found in

normal cells, and some are induced by stress conditions, such as heat. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zuany-Amorim, C., Hastewell, J.

& Walker, C. Toll-like receptors as potential therapeutic targets for multiple diseases. _Nat Rev Drug Discov_ 1, 797–807 (2002). https://doi.org/10.1038/nrd914 Download citation * Issue

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