ReviewToll-like receptors: key mediators of microbe detection
Introduction
A remarkable feature of the innate immune system is its capacity to recognize a broad spectrum of pathogens using a repertoire of invariant receptors. These receptors recognize an array of microbial components, comprising combinations of sugars, proteins and lipids, as well as distinct nucleic acid motifs. Unifying features of these targets include their highly conserved structures, which are not easily altered by microbes to evade detection, and their presence on broad classes of organisms.
Many different types of receptors participate in microbe detection [1], and an exciting development in our understanding of pathogen recognition has been the discovery that the Toll-like receptor (TLR) family mediates recognition of microbial targets in several organisms including humans, mice and flies 2., 3., 4.. Recent developments in the field have modified our view of the role of TLRs in detecting microbes (Fig. 1).
Identification of TLR4 as the receptor for Gram-negative bacterial lipopolysaccharide (LPS) and TLR2 as the receptor for Gram-positive peptidoglycan and lipopeptides led to an initial model in which each of the additional TLRs were expected to recognize similarly broad classes of other microbes (e.g. parasites or viruses). With the discovery of additional ligands for TLR2 and TLR4, and the discovery of ligands for several other TLRs, our model has evolved into one in which immune cells use many different TLRs to detect several features of an organism simultaneously; this permits information about the nature of the microbe to be transmitted into the cell. With this information, the innate immune system can direct a response that is tailored to the threat (Fig. 1).
Here we review the growing repertoire of TLR ligands, recent developments in elucidating the mechanisms underlying TLR signal transduction, and the evolution of our understanding of the role of TLRs in defense.
Section snippets
TLR4
As the receptor for Gram-negative bacterial LPS, TLR4 is the best-characterized member of the TLR family [3]. Initially, positional cloning of the lps gene in the LPS hypo-responsive C3H/HeJ mouse revealed a proline to histidine mutation in the signaling domain of TLR4 5., 6., and subsequent specific deletion of the gene confirmed the role of TLR4 in mediating inflammatory signals from LPS [7]. Since then, many of the mechanisms underlying LPS detection by TLR4 have been elucidated. LPS is
Signaling
The intracellular signaling pathways activated by TLRs share much in common with IL-1R signaling owing to their conserved TIR (Toll/IL-1R homology) domains. Activation of signaling through TIR domains results in recruitment of the cytoplasmic adaptor molecule MyD88 (which itself has a TIR domain), activation of serine/threonine kinases of the IRAK family, and ultimately degradation of Iκ-B and translocation of NF-κB to the nucleus (Fig. 2) 2., 3., 44., 45..
Recently, an additional molecule,
TLR-induced defense mechanisms
In addition to upregulating the production of important inflammatory mediators such as TNF-α and IL-12, activation of TLRs also results in upregulation of microbial killing mechanisms. One important mechanism is the production of reactive nitrogen species, and many studies have linked TLR signaling to the induction of iNOS mRNA and the production of NO 30•., 38., 56., 57., but production of iNOS is not always sufficient for killing. Modlin and co-workers [58•] have observed that whereas TLR2
Conclusions
The functions that have been described for five of the ten mammalian TLRs published to date indicate that TLRs play a central role in inflammation and innate immune defense and are important regulators of adaptive immunity. These findings have sparked renewed interest in the mechanisms of innate detection of microbes and we expect the field to continue to evolve rapidly with the definition of additional ligands, additional signaling mechanisms and a more complete understanding of the role of
Update
Macrophages are activated by many viruses through detection of dsRNA. Recent characterization of TLR3 knockout mice has implicated TLR3 in the recognition of dsRNA [70••]. Expression of TLR3 in cells unresponsive to dsRNA confers responsiveness and macrophages from mice lacking TLR3 are deficient in dsRNA-induced activation. Thus, like bacteria and yeast, multiple TLRs (TLR4 and TLR3) participate in the recognition of viruses.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
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2022, Experimental ParasitologyCitation Excerpt :Donnelly et al. (2010) mentioned that S. mansoni cysteine proteases limit the release of inflammatory mediators such as nitric oxide, IL-6, TNF-α, and IL-12 from macrophages by blocking TLR4 MyD88-independent, TRIF-dependent signaling pathway. The difference in TLR4 expression patterns in different organs may be explained by the several signaling pathways that can emerge from a single TLR's interaction with various supplementary pattern recognition receptors (PRRs) and the signaling adaptor molecules they recruit (Underhill and Ozinsky, 2002). Also, it may be related to the innate immune response's adaptation to the different microbial environments that each tissue encounters (Pioli et al., 2004).