Review paper
Toll-like receptor signaling in bony fish

https://doi.org/10.1016/j.vetimm.2009.09.021Get rights and content

Abstract

The innate immune system constitutes an efficient defense against invading microbial pathogens. Toll-like receptors (TLRs) eventually alert vertebrates about the presence of pathogens and elicit the immune responses. To date, 17 different TLRs have been identified in more than a dozen different fish species. Numerous studies revealed that specific piscine TLRs share functional properties with their mammalian counterparts. Nevertheless, remarkable distinct features of teleostean Toll-like receptor cascades have been discovered. A soluble TLR5 factor in rainbow trout for example might amplify danger signaling of membrane-bound TLR5 in a positive feed loop. Piscine TLR3 detects viral and additionally bacterial molecular patterns in contrast to mammalian TLR3. Regarding TLR4, the functional spectrum of this teleostean receptor is also different from its mammalian orthologue. While signaling quite similar as the mammalian counterpart in some fish species, it may down-regulate TLR activation in others or was even lost during evolution. The orthologues of human TLR6 and TLR10 are also absent in teleosts. Some piscine TLRs are encoded by duplicated genes, for example salmonid TLR22. TLR22 is found in several fish species but only as a non-functional pseudogene in man. Additional distinct features of the TLR pathway in bony fish suggest its specific optimization for the aquatic environment. This review summarizes studies characterizing TLRs from several teleost species and discusses features of piscine TLR signaling on the background of the respective mammalian knowledge.

Introduction

Organisms are permanently exposed to microbial pathogens. Innate immune reactions contribute to the fundamental defense strategy of bony fish in response to various infectious agents. Several innate immune parameters in teleost fish are more active and show more diversity than comparable components of mammals (Magnadottir, 2006). A crucial step for the initiation of immune defense mechanisms is the recognition of danger signals and the subsequent activation of signaling cascades (Arancibia et al., 2007). Key activators are the pattern recognition receptors (PRR) sensing conserved microbial features, the so-called “pathogen-associated molecular patterns” (PAMPs) (Medzhitov, 2007). The PRRs detect also endogenous structures released after tissue traumata, i.e. “damage-associated molecular patterns” (DAMPs) (Matzinger, 2002). PRRs represent evolutionary conserved receptors including Toll-like receptors (TLRs) that are structurally related to interleukin-1 receptors (IL1Rs). The IL1R proteins are defined by their extracellular immunoglobulin-like domains (Subramaniam et al., 2004). In contrast, the extracellular domain of TLRs is composed of up to 26 leucine-rich repeats (LRR) flanked by N-terminal and C-terminal cap motifs. These LRR consist of 20–30 amino acids folding into a horseshoe-like conformation (Bell et al., 2003). The structural diversity of LRR folding allows a broad range of binding specificities for certain agonists. The intracellular Toll-like/interleukin-1 receptor resistance (TIR) domain is characteristic for both IL1Rs and TLRs (O’Neill, 2008). Upon receptor activation, the mammalian TIR domain signaling complex is formed between this receptor domain and adequate adaptor molecules, mainly the myeloid differentiation primary response protein 88 (MyD88) (McGettrick and O’Neill, 2004). MyD88 and the interleukin-1 receptor-associated kinase (IRAK) 4 share a death domain conveying the contact between both proteins. Subsequently, IRAK4 phosphorylates the downstream kinase IRAK1, recruiting TRAF6 (tumor necrosis factor receptor-associated factor 6) (Cao et al., 1996). This factor in turn binds and activates the TAB1/TAK1/TAB2 complex. Consecutively, TAK1 is able to phosphorylate the kinase of the NF-κB inhibitory complex which then again phosphorylates the NF-κB inhibitor IκB. The latter is targeted for degradation (Doyle and O’Neill, 2006). Beside this MyD88-dependent pathway, MyD88-independent signaling cascades exist (Brikos and O’Neill, 2008) employing alternative adaptors. TLR4, for example, recruits also TIRAP (TIR domain-containing adaptor protein, also termed as Mal) (Fitzgerald et al., 2001) or the two factors TICAM1 (TIR domain-containing adaptor molecule 1, also termed as TRIF) (Oshiumi et al., 2003a), and TICAM2 (also termed as TRAM) (Oshiumi et al., 2003b). In contrast to TLR4, TLR3 interacts directly with TICAM1. SARM (sterile alpha and HEAT/Armadillo motifs-containing protein) is a MyD88-substituting protein with unknown function (O’Neill et al., 2003). Eventually, the TLR signaling cascade activates mainly members of the nuclear factor-κB (NF-κB) family and CCAAT/enhancer binding proteins (C/EBP). These transcription factors regulate the expression of immunorelevant genes.

In recent years, several factors have been identified that negatively regulate the mammalian TLR signaling cascade (Liew et al., 2005). Toll-interacting protein (Tollip) was the first investigated inhibitor (Burns et al., 2000, Bulut et al., 2001) limiting the TLR2- and TLR4-dependend NF-κB activation. Tollip is reported to decrease the autophosphorylation level of IRAK1. Upon TLR stimulation, IRAK1 causes phosphorylation of Tollip, which in turn ubiquitylates IRAK1 for degradation by the proteasome. Control mechanisms are essential to limit the production of pro-inflammatory mediators and to protect against immunopathological effects.

Section snippets

Toll-like receptors in teleosts

Toll receptors have originally been identified in Drosophila melanogaster as essential factors establishing dorsoventral polarity during early embryogenesis (Anderson et al., 1985). Subsequently, it has been found that flies with a mutant Toll gene are highly susceptible to fungal infection, because this mutation impairs the production of specific anti-fungal peptides (Lemaitre et al., 1996). Human TLR4 was the first mammalian receptor that has been identified as an orthologue of Toll1 from D.

Downstream factors of piscine TLR signaling

TLR adaptor molecules. The various TLRs identified from different fish species encouraged the search for further factors of the piscine Toll-like receptor activation cascade. Several investigations revealed that TLR signaling in bony fish depends on MyD88. As early as in 2004, Jault et al. (2004) postulated that MyD88 as well as Mal, TICAM and SARM are encoded in the zebrafish genome. Already zebrafish embryos express MyD88, Mal, TICAM, and SARM, whereas MyD88 expression is markedly higher in

Conclusions

Toll-like receptors are key components of the innate immune system, hence crucially involved in pathogen defense. A collection of different TLRs, each specific for a broad range of PAMPs and DAMPs, is common for all vertebrate and even invertebrate species. Seventeen different TLR types have been identified in bony fish to date, but the number of particular TLRs might differ among teleostean species. On the one hand, fishes encode Toll-like receptors representing true orthologues to their

Acknowledgements

We thank Prof. Dr. E. Siegl for valuable ideas and suggestions. The European Community through the EADGENE Network of Excellence also contributed to this survey.

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