Toll-like receptor

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Toll-like receptors (TLRs) are type I transmembrane proteins that recognize microbes once they have breached physical barriers such as the skin or intestinal tract mucosa, and activate immune cell responses. They are believed to play a key role in the innate immune system. TLRs are a type of pattern recognition receptors (PRRs) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs) . However, there are some exceptions to this general rule. TLRs are present in vertebrates (including fish, amphibians, reptiles and birds and mammals) as well as in invertebrates (such of the insect Drosophila where they have been extensively studied). Molecular building blocks of the TLRs are represented in bacteria and in plants, and in the latter kingdom, are well known to be required for host defense against infection. The TLRs thus appear to be one of the most ancient, conserved components of the immune system.

Contents 1 The Discovery of TLRs 2 The TLR family 3 TLR ligands 4 TLR signaling 5 Activation and effects 6 Danger model 7 Drugs interacting with TLRs 8 References 9 Further reading 10 External links

[edit] The Discovery of TLRs

Their name derives from homology to a family of molecules in the fruit fly Drosophila melanogaster, the prototypic member of which was called Toll. ("Toll," in German, means "amazing" or "cool" [English slang]). In fruit flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, Toll was found by Jules Hoffmann and his colleagues to have a role in the fly's immunity to fungal infection^[1]. By the time this discovery was made, Toll-like receptors had been recognized in mammals for more than two years. First reported by Nomura and colleagues in 1994^[2] and mapped to a chromosome by Taguchi and colleagues in 1996^[3], "TIL" (in current terminology TLR1) was the first TLR to be identified. Because the immune function of Toll in Drosophila was not then known, it was assumed that TIL might participate in mammalian development. Moreover, it was known that a molecule with a clear role in immune function in mammals, the interleukin-1 (IL-1) receptor, had homology to Toll, in that the cytoplasmic portions of both molecules were similar (first noted by Nick Gay in 1991)^[4].

Charles Janeway and colleagues identified a second TLR paralogue in 1997^[5], naming it "h-Toll" (now TLR4). Taking note of Hoffmann's work, they suggested that in mammals, h-Toll might "activate adaptive immunity." The precise function of TLR4 was discovered in 1998 by Bruce Beutler and colleagues, who used a genetic technique (positional cloning) to prove that TLR4 serves as the receptor for bacterial lipopolysaccharide (also known as "endotoxin," or LPS)^[6]. LPS had by then been known for its strong inflammatory and immunostimulatory effects for more than 100 years. By mapping mutations that caused LPS insensitivity in mice, Beutler and colleagues determined that TLR4 was specifically required for the perception of LPS. This observation strongly suggested that each of the TLRs in mammals might recognize a small set of signature molecules produced by microbes in the course of infection. It now appears that this inference was correct, and that the mammalian TLRs are among the key proteins that enable mammals to sense infection and mount an immune response. Mice that cannot signal via TLRs are severely immunocompromised. On the other hand, it is also clear that the TLRs are a key conduit for the initiation of inflammation, and the most proximal cause of septic shock: a serious condition that often complicates systemic infection.

[edit] The TLR family

It has been estimated that most mammalian species have between ten and fifteen types of Toll-like receptors. Thirteen TLRs (named simply TLR1 to TLR13) have been identified in humans and mice together, and equivalent forms of many of these have been found in other mammalian species^[7][8][9]. However, equivalents of certain TLR found in humans are not present in all mammals. For example, a gene coding for a protein analogous to TLR10 in humans is present in mice, but appears to have been damaged at some point in the past by a retrovirus. On the other hand, mice express TLRs 11, 12, and 13, none of which is represented in humans. Other mammals may express TLRs which are not found in humans. This may complicate the process of using experimental animals as models of human innate immunity.

[edit] TLR ligands

Because the specificity of Toll-like receptors (and other innate immune receptors) cannot easily be changed in the course of evolution, these receptors recognize molecules that are constantly associated with threats (i.e. pathogen or cell stress), that are not subject to mutation, and are highly specific to these threats (i.e. cannot be mistaken for self molecules). Pathogen associated molecules that meet this requirement are usually critical to the pathogen's function and cannot be eliminated or changed through mutation; they are said to be evolutionarily conserved. Well conserved features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses or the unmethylated CpG islands of bacterial and viral DNA; and certain other RNA and DNA. For most of the TLRs, Ligand recognition specificity has now been established by gene targeting (also known as "gene knockout"): a technique by which individual genes may be selectively deleted in mice. This work has been pursued most actively in the laboratories of Shizuo Akira and Richard Flavell^[10][11]. See the table below for a summary of known TLR ligands.

[edit] TLR signaling

TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4's recognition of LPS, which requires MD-2. CD14 and LPS Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.

The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, in the laboratory of Bruce Beutler, random germline mutagenesis with ENU has been used to decipher the TLR signaling pathways. When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram^[12][13][14]. The adapters activate other molecules within the cell, including certain protein kinases (IRAK1, IRAK4, TBK1, and IKKi) that amplify the signal, and ultimately lead to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitutes one of the most powerful and important gateways for gene modulation.

Summary of Known Mammalian Toll-like Receptors

Receptor	Ligand(s)	Adapter(s)	Location
TLR 1	triacyl lipoproteins	MyD88/MAL	cell surface
TLR 2	lipoproteins; gram positive peptidoglycan; lipoteichoic acids; fungi; viral glycoproteins	MyD88/MAL	cell surface
TLR 3	double-stranded RNA (as found in certain viruses), poly I:C	TRIF	cell compartment
TLR 4	lipopolysaccharide; viral glycoproteins	MyD88/MAL/TRIF/TRAM	cell surface
TLR 5	flagellin	MyD88	cell surface
TLR 6	diacyl lipoproteins	MyD88/MAL	cell surface
TLR 7	small synthetic compounds; single-stranded RNA	MyD88	cell compartment
TLR 8	small synthetic compounds; single-stranded RNA	MyD88	cell compartment
TLR 9	unmethylated CpG DNA	MyD88	cell compartment
TLR 10	unknown	unknown	cell surface
TLR 11	Profilin	MyD88	cell surface
TLR 12	unknown	unknown	?
TLR 13	unknown	unknown	?

[edit] Activation and effects

Following activation by ligands of microbial origin, several reactions are possible. Immune cells can produce signalling factors called cytokines which trigger inflammation. In the case of a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells. In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death (apoptosis). Immune cells that have detected a virus may also release anti-viral factors such as interferons.

The discovery of the Toll-like receptors finally identified the innate immune receptors that were responsible for many of the innate immune functions that had been studied for many years. Interestingly, TLRs seem only to be involved in the cytokine production and cellular activation in response to microbes, and do not play a significant role in the adhesion and phagocytosis of microorganisms.

[edit] Danger model

More recently TLRs have been suspected of binding to non-pathogen associated factors produced during disease, stress, and trauma; including molecules such as fibrinogen (involved in blood clotting post-trauma) and heat shock proteins (HSPs) (generated in heat stress, including pathogen response fevers). This is based upon Polly Matzinger's "Danger Model" of immunity, which suggests that these molecular signatures are recognised as associated with either an increased risk of disease, or disease itself, and put the immune system on alert through TLR activation. However, this model is controversial.

[edit] Drugs interacting with TLRs

Imiquimod (cardinally used in dermatology), and its successor R848, are ligands for TLR7 and TLR8 ^[15].

[edit] References

1. ^ Lemaitre,B., Nicolas,E., Michaut,L., Reichhart,J.M., and Hoffmann,J.A. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973-983.
2. ^ Nomura,N., Miyajima,N., Sazuka,T., Tanaka,A., Kawarabayasi,Y., Sato,S., Nagase,T., Seki,N., Ishikawa,K., and Tabata,S. 1994. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line KG-1. DNA Res. 1:27-35.
3. ^ Taguchi,T., Mitcham,J.L., Dower,S.K., Sims,J.E., and Testa,J.R. 1996. Chromosomal localization of TIL, a gene encoding a protein related to the Drosophila transmembrane receptor Toll, to human chromosome 4p14. Genom. 32:486-488.
4. ^ Gay NJ, Keith FJ. Drosophila Toll and IL-1 receptor. Nature. 1991 May 30;351(6325):355-6.
5. ^ Medzhitov,R., Preston-Hurlburt,P., and Janeway,C.A., Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394-397.
6. ^ Poltorak,A., He,X., Smirnova,I., Liu,M.-Y., Van Huffel,C., Du,X., Birdwell,D., Alejos,E., Silva,M., Galanos,C. et al 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085-2088.
7. ^ Du,X., Poltorak,A., Wei,Y., and Beutler,B. 2000. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur. Cytokine Netw. 11:362-371.
8. ^ Chuang,T.H., and Ulevitch,R.J. 2000. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur. Cytokine Netw. 11:372-378.
9. ^ Tabeta,K., Georgel,P., Janssen,E., Du,X., Hoebe,K., Crozat,K., Mudd,S., Shamel,L., Sovath,S., Goode,J. et al 2004. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl Acad. Sci. U. S. A 101:3516-3521.
10. ^ Hoebe,K., Du,X., Georgel,P., Janssen,E., Tabeta,K., Kim,S.O., Goode,J., Lin,P., Mann,N., Mudd,S. et al 2003. Identification of Lps2 as a key transducer of MyD88-independent TIR signaling. Nature 424:743-748.
11. ^ Hemmi,H., Takeuchi,O., Kawai,T., Kaisho,T., Sato,S., Sanjo,H., Matsumoto,M., Hoshino,K., Wagner,H., Takeda,K. et al 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740-745.
12. ^ Yamamoto,M., Sato,S., Hemmi,H., Hoshino,K., Kaisho,T., Sanjo,H., Takeuchi,O., Sugiyama,M., Okabe,M., Takeda,K. et al 2003. Role of adapter TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640-643.
13. ^ Yamamoto,M., Sato,S., Hemmi,H., Uematsu,S., Hoshino,K., Kaisho,T., Takeuchi,O., Takeda,K., and Akira,S. 2003. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4:1144-1150.
14. ^ Yamamoto,M., Sato,S., Hemmi,H., Sanjo,H., Uematsu,S., Kaisho,T., Hoshino,K., Takeuchi,O., Kobayashi,M., Fujita,T. et al 2002. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324-329.
15. ^ Peter Fritsch: "Dermatologie und Venerologie" (German), 2nd ed. 2004, Springer ,ISBN 3-540-00332-0

[edit] Further reading

• Genetic analysis of host resistance: Bruce Beutler, et al., "Toll-like receptor signaling and immunity at large." Annu Rev Immunol. 2006;24:353-89
• Daniel R Goldstein, "Toll-like receptors and other links between innate and acquired alloimmunity", Current Opinion in Immunology 16(5):538-544, October 2004 (DOI:10.1016/j.coi.2004.08.001)
• Luke A. J. O'Neill, "Immunity's Early-Warning System", Scientific American 292(1):38-45, January 2005
• Dunne A, O'Neill LA, "The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense", Sci STKE. 2003 Feb 25;2003(171):re3. online version

[edit] External links

• Toll-like receptor

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