Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk

The complete sequences of Takifugu Toll-like receptor (TLR) loci and gene predictions from many draft genomes enable comprehensive molecular phylogenetic analysis. Strong selective pressure for recognition of and response to pathogen-associated molecular patterns has maintained a largely unchanging TLR recognition in all vertebrates. There are six major families of vertebrate TLRs. This repertoire is distinct from that of invertebrates. TLRs within a family recognize a general class of pathogen-associated molecular patterns. Most vertebrates have exactly one gene ortholog for each TLR family. The family including TLR1 has more speciesspecific adaptations than other families. A major family including TLR11 is represented in humans only by a pseudogene. Coincidental evolution plays a minor role in TLR evolution. The sequencing phase of this study produced finished genomic sequences for the 12 Takifugu rubripes TLRs. In addition, we have produced >70 gene models, including sequences from the opossum, chicken, frog, dog, sea urchin, and sea squirt. coincidental evolution ͉ multigene family ͉ concerted evolution T he Toll-like receptor (TLR) multigene family encodes important recognition receptors of the innate immune system that have been conserved in both the invertebrate and vertebrate lineages (1, 2). TLRs recognize a variety of endogenous and exogenous ligands; many of the latter are conserved molecules essential for pathogen survival. TLR genes have been recognized in a number of vertebrate genomes, and many partial and full-length sequences are available. Recent additions include draft predictions from the Japanese pufferfish Takifugu rubripes (3), the zebrafish Danio rerio (4-6), and the chicken Gallus gallus (7), and partially or fully sequenced mRNAs, including one from the goldfish Carassius auratus (8), several from the Japanese flounder Paralichthys olivaceus (9), and several from the rainbow trout Oncorhynchus mykiss (10). These papers provide incremental molecular phylogenetic analyses, and several reviews are available (11-13). Additionally, the draft genomes of the frog Xenopus tropicalis, chicken G. gallus, and opossum Monodelphis domesticus are now available. We present a complete molecular phylogenetic analysis of the known vertebrate TLR genes in the context of the complete genomic sequences of the T. rubripes TLRs. MethodsSequencing and Assembly. A draft genome sequence of T. rubripes was obtained by pairwise shotgun sequencing (14) through the efforts of an international collaboration (15). Sequence finishing was performed in part as described (16), with additional details provided in Supporting Text, which is published as supporting information on the PNAS web site.Bioinformatics. TLRs were identified as genes coding for both an N-terminal leucine-rich repeat (LRR) domain and a C-terminal Toll-IL-resistance (TIR) domain. To form the basis of our study, vertebrate sequences from the nonredundant DDBJ͞EMBL͞ NCBI database (GenBank) were identified by similarity to known TLRs (Data Set 1, which is...

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“…LeBouder et al (33) report a soluble form of mammalian TLR2. A polymorphic form of TLR5 could conceivably be secreted (34).…”

Section: Discussionmentioning

confidence: 99%

The evolution of vertebrate Toll-like receptors

Roach

Glusman

Rowen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

1,028

816

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“…Therefore, TLR-mediated signaling events contain negative feedback mechanisms. For example, soluble decoy TLRs (sTLR-2/-4) antagonize ligand binding and potently attenuate TLR-induced effector functions (38,39). Different intracellular negative regulators have been uncovered such as MyD88s, IRAKM, TOLLIP, A20, SOCS1, PI3K, and NOD2 (40 -42).…”

Section: Discussionmentioning

confidence: 99%

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Torgler

Bongfen

Romero

et al. 2008

The Journal of Immunology

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Plasmodium sporozoites traverse several host cells before infecting hepatocytes. In the process, the plasma membranes of the cells are ruptured, resulting in the release of cytosolic factors into the microenvironment. This released endogenous material is highly stimulatory/immunogenic and can serve as a danger signal initiating distinct responses in various cells. Thus, our study aimed at characterizing the effect of cell material leakage during Plasmodium infection on cultured mouse primary hepatocytes and HepG2 cells. We observed that wounded cell-derived cytosolic factors activate NF-κB, a main regulator of host inflammatory responses, in cells bordering wounded cells, which are potential host cells for final parasite infection. This activation of NF-κB occurred shortly after infection and led to a reduction of infection load in a time-dependent manner in vitro and in vivo, an effect that could be reverted by addition of the specific NF-κB inhibitor BAY11-7082. Furthermore, no NF-κB activation was observed when Spect−/− parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-κB activation causes the induction of inducible NO synthase expression in hepatocytes, and this is, in turn, responsible for a decrease in Plasmodium-infected hepatocytes. Furthermore, primary hepatocytes from MyD88−/− mice showed no NF-κB activation and inducible NO synthase expression upon infection, suggesting a role of the Toll/IL-1 receptor family members in sensing cytosolic factors. Indeed, lack of MyD88 significantly increased infection in vitro and in vivo. Thus, host cell wounding due to parasite migration induces inflammation which limits the extent of parasite infection.

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“…It is assumed that specific insertions in LRR of each TLR provide specific ligand binding sites (23) But not only pathogens try to repress TLR activation, also a variety of endogenous mechanisms exist to contain the pro-inflammatory TLR cascade. A soluble form of TLR2 was found to be expressed in humans and soluble TLR4 was measured in mice (30,31). These soluble forms might function as decoy receptors, blocking TLR responses by binding to coreceptors or ligands.…”

Section: Toll-like Receptors At a Glancementioning

confidence: 99%

TLRs and chronic inflammation

Ospelt

Gay

2010

The International Journal of Biochemistry & Cell Biology

156

127

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After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated. TLRs and chronic inflammation Abstract:After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases.In this review, an overview of the currently known TLRs and their signaling pathways isgiven and reports about their expression and activation in chronic inflammatory diseases are recapitulated.2

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Soluble Forms of Toll-Like Receptor (TLR)2 Capable of Modulating TLR2 Signaling Are Present in Human Plasma and Breast Milk

Cited by 297 publications

References 46 publications

The evolution of vertebrate Toll-like receptors

The evolution of vertebrate Toll-like receptors

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

TLRs and chronic inflammation

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