Toll-like receptors as potential therapeutic targets for multiple diseases

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 signalling pathways that are similar to those that are engaged by interleukin-1 (IL-1), leading to the nuclear translocation of nuclear factor-κB (NF-κB) and the subsequent transcriptional activation of numerous pro-inflammatory genes.Blocking TLR function as a potential therapeutic strategy is obvious when bacteria and bacterial products, through exaggerated TLR responses, 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.