Toll-like Receptors: the sentinels of the innate immune system
Toll-Like receptors (TLRs) play a critical role in early innate immunity to invading pathogens by sensing microorganisms. These evolutionary conserved receptors, homologues of the Drosophila Toll gene, recognize highly conserved structural motifs only expressed by microbial pathogens, called pathogen-associated microbial patterns (PAMPs). PAMPs include various bacterial cell wall components such as lipopolysaccharides (LPS), peptidoglycans and lipopeptides, as well as flagellin, bacterial DNA and viral double-stranded RNA. Stimulation of TLRs by PAMPs initiates a signaling cascade that involves a number of proteins, such as MyD88 and IRAK[1]. This signaling cascade leads to the activation of the transcription factor NF-κB which induces the secretion of pro-inflammatory cytokines and effector cytokines that direct the adaptive immune response.
TLRs are transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic tail that contains a conserved region called the Toll/IL-1 receptor (TIR) domain. TLRs are predominantly expressed in tissues involved in immune function, such as spleen and peripheral blood leukocytes, as well as those exposed to the external environment such as lung and the gastrointestinal tract.
Ten human and nine murine TLRs have been characterized so far and only five of them have had their natural ligands identified[2].
TLR2 is essential for the recognition of a variety of PAMPs, including bacterial lipoproteins, peptidoglycan, and lipoteichoic acids.
TLR3 is implicated in virus-derived double-stranded RNA.
TLR4 is predominantly activated by lipopolysaccharide.
TLR5 detects bacterial flagellin and TLR9 is required for response to unmethylated CpG DNA.
Recently, TLR7 and TLR8 have been shown to recognize small synthetic antiviral molecules[3].
Furthermore, in many instances, TLRs require the presence of a co-receptor to initiate the signaling cascade. One example is TLR4 which interacts with MD2 and CD14, a protein that exists both in soluble form and as a GPI-anchored protein, to induce NF-κB in response to LPS stimulation[4].
Current knowledge of the TLRs indicates that these receptors are essential elements in host defense against pathogens by activating the innate immunity a prerequisite to induction of adaptive immunity. The growing interest on TLRs should bring a more complete understanding of the role of TLR-mediated responses and increase our range of weapons to treat infectious and immune diseases.
REFERENCES
1. Medzhitov R. et al., 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature, 388(6640):394-7
2. Underhill DM. and A. Ozinsky, 2002. Toll-like receptors: key mediators of microbe detection. Curr Opin Immunol, 14:103-10
3. Jurk M. et al., 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol, 3(6):499
4. Jiang Q. et al., 2000. Lipopolysaccharide induces physical proximity between CD14 and toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-kappa B. J Immunol, 165(7):3541-4