Great-like receptors

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Comparison of the Toll signaling pathway in mammals, shrimp, and fruit flies

Toll-like receptors (TLR briefly, English toll-like receptor ) are structures of the innate immune system (innate immunity) and belong to a group of receptors , the PRRs (Pattern-Recognition Receptors) . They are used to recognize PAMPs (Pathogen-Associated Molecular Patterns) , which are structures that occur exclusively on or in pathogens , and control the corresponding activation of genes . This initiates and modulates the activation of the “antigen-specific acquired immune system” (antigen-specific acquired immunity) . The innate defense system is able to distinguish between “self” and “not self” through the “toll-like receptors”. TLRs are generally expressed in dendritic cells and macrophages, with little to no expression in epithelial cells.

The name toll-like receptor (referred to in German-language literature as signal transduction- mediating PRRs or rarely also as toll-like receptor ) is derived from a protein in Drosophila melanogaster , which the research group around Nobel Prize winner Christiane Nüsslein-Volhard was so enthusiastic about was that she humorously called it great after the German expression . The moment that gave the great gene of the fruit fly its name was when she was sitting across from her colleague Eric Wieschaus at a double microscope that allows two people to examine the same object at the same time. “One day when we saw a mutant embryo whose development was ventralized, we were both completely surprised and spontaneously shouted 'great'. Until then we only knew dorsalized embryos ”. TLRs consist of proteins that resemble Toll, i.e. are toll-like .

Since the discovery of the first toll-like receptor in the mid-1990s, new variants have been discovered again and again in humans and animals . TLRs are found in all vertebrates but also in simpler organisms , such as Drosophila melanogaster , which suggests that this is an evolutionarily very old system. Most species have more than ten different (known) TLRs, some types e.g. B. occur in the mouse , but not in humans.

TLRs recognize various functional components of viruses , bacteria and fungi and can thus trigger biochemical reaction chains in the cells that serve to defend themselves against these pathogens.

Discovery of TLRs

Great signaling pathway from Drosophila melanogaster

When microorganisms were first identified as the cause of infectious diseases , it was clear that multicellular organisms must be able to recognize them, and that in order to do this, it is necessary to recognize molecular structures typical of microorganisms. A large body of literature, spanning much of the 20th century, is devoted to key molecules and their receptors. More than 100 years ago, Richard Pfeiffer , a student of Robert Koch , coined the term ' endotoxin ' to name a substance that was produced by gram-negative bacteria and that led to fever and shock in animal experiments. In the decades that followed, the endotoxins were chemically characterized and identified as lipopolysaccharides (LPS), which are produced by most gram-negative bacteria. It has been shown that other molecules (bacterial lipopeptides, flagellins and unmethylated DNA ) also lead to an immune response . Logically it was concluded from this that there must be receptors that are able to induce an immune response for such molecular structures. However, these were not found for many years.

In the mid-1990s, research in the developmental biology of Drosophila melanogaster discovered by chance that toll-negative mutants are very susceptible to fungal attack. This observation initiated a targeted search for similar proteins in mammalian cells. In 1994 Nomura and colleagues were able to find the first human TLR, which Taguchi and colleagues were able to assign to a chromosome in 1996 . This shows that the immune response mediated via toll-like receptors is an evolutionarily very old form that is genetically highly conserved. Since the role of TLRs in immune defense was not yet known at the time, it was assumed that TLR1 would play a role in mammalian developmental biology. In 1997, Charles Janeway and Ruslan Medzhitov showed that a toll-like receptor, when artificially bound to appropriate antibodies, can activate certain genes that are necessary for an adaptive immune response. The role of TLR4 as an LPS receptor was discovered by Bruce A. Beutler and colleagues. Over time, the ligands of the other TLRs were also determined. Shizuo Akira played a central role in this.

Structure and ligands

The common structural features of all toll-like receptors are the N-terminal leucine-rich LRR sequences ( leucine-rich repeats ) and the TIR domain (Toll / IL-1R homology domain) . The different TLRs can each identify different PAMPs (Pathogen Associated Molecular Patterns) through direct interaction with the respective membrane surface of the pathogen. TLR3, TLR7, TLR8 and TLR9 are located on the membrane of endosomes or endolysosomes, while the remaining toll-like receptors are located on the cell membrane.

TLR2 recognizes many components of bacteria, mycoplasma, fungi and viruses. This also includes the lipoproteins of bacteria and mycoplasmas. The detection takes place in that TLR2 forms a heterodimer with either TLR1 or TLR6. The resulting TLR1 / TLR2 and TLR6 / TLR2 complexes recognize triacyl and diacyllipoproteins. The activation of TLR2 leads to the release of a number of cytokines . Alpha interferon (IFN-α) is only partially released. It is generally assumed that the release of IFN-α depends on the cell type. TLR10 is similar in its primary structure (sequence match) to TLR1 and TLR6, but the ligand is not yet known. TLR4 can recognize lipopolysaccharide (LPS) on the cell surface along with MD2 (myeloid differentiation factor 2) . LPS is a substance from the outer membrane of gram-negative bacteria and is used in animal models for the limited simulation of acute infections. In the detection of LPS, two TLR-4-MD2-LPS complexes work together to form a TLR-4 homodimer.

TLR5 is mainly expressed in the lamina propria , where it recognizes bacterial flagellin. As an immune response, TLR5 induces the differentiation of B cells into IgA-producing blood cells and of T cells into antigen-specific Th17 and Th1 cells. TLR11, which only occurs in mice but not in humans, shows great similarities to TLR5. It recognizes a profilin-like molecule derived from the intracellular protozoan Toxoplasma gondii . A number of TLRs, including TLR3, TLR7, TLR8, and TLR9, recognize nucleic acids derived from viruses or bacteria. Activation of these TLRs leads to the formation of alpha interferon and other inflammatory cytokines . TLR3 detects viral double-stranded RNA in the endolysosome. The dsRNA binds to the N-terminal and the C-terminal end of the LRR sequence.

receptor Ligands Origin of the ligands Adapter protein of the TLR Cellular localization Cell types
TLR 1 Various triacyl lipopeptides Bacterial lipoprotein MyD88 / MAL Cell surface
TLR 2 Various glycolipids Bacterial peptidoglycans MyD88 / MAL Cell surface
Various lipopeptides and proteolipids Bacterial peptidoglycans
Lipoteichoic acid Gram positive bacteria
HSP70 Host cells
Zymosan ( beta-glucan ) Mushrooms
Numerous others
TLR 3 Double stranded RNA , poly I: C Viruses TRIF Cell compartment
  • Dendritic cells
  • B lymphocytes
TLR 4 Lipopolysaccharide , Eritoran Gram negative bacteria MyD88 / MAL / TRIF / TRAM Cell surface
Multiple heat shock proteins Bacteria and host cells
Fibrinogen Host cells
Heparan sulfate fragments Host cells
Hyaluronic acid fragments Host cells
nickel
Various opioids
TLR 5 Bacterial flagellin bacteria MyD88 Cell surface
  • Monocytes / macrophages
  • A subset of the dendritic cells
  • Intestinal epithelial cells
  • Breast cancer cells
Profilin Toxoplasma gondii
TLR 6 Various diacyl lipopeptides Mycoplasma MyD88 / MAL Cell surface
  • Monocytes / macrophages
  • Mast cells
  • B lymphocytes
TLR 7 Imidazoquinoline Low molecular weight synthetic substances MyD88 Cell compartment
  • Monocytes / macrophages
  • Plasmacytoid dendritic cells
  • B lymphocytes
Loxoribine (a guanosine analog )
Bropirimine
Imiquimod , resiquimod
Single stranded RNA RNA viruses
TLR 8 Low molecular weight synthetics, single-stranded viral RNA, resiquimod, phagocytosed bacterial RNA MyD88 Cell compartment
TLR 9 Unmethylated CpG oligonucleotides (DNA) Bacteria, dna viruses MyD88 Cell compartment
  • Monocytes / macrophages
  • Plasmacytoid dendritic cells
  • B lymphocytes
TLR 10 Triacylated lipopeptides unknown Cell surface
  • B lymphocytes
  • Intestinal epithelial cells
  • Monocytes / macrophages
TLR 11 Profilin Toxoplasma gondii MyD88 Cell compartment
TLR 12 Profilin Toxoplasma gondii MyD88 Cell compartment
  • Neurons
  • Plasmacytoid dendritic cells
  • Classic dendritic cells
  • Macrophages
TLR 13 Bacterial ribosomal RNA sequence CGGAAAGACC (unmethylated) Viruses, bacteria MyD88, TAK-1 Cell compartment
  • Monocytes / macrophages
  • Classic dendritic cells

The intracellular signal cascade

Signaling pathway of TLR 4. Unknown mechanisms are shown with dashed gray lines

The chemoattractor proteins "C3a" and "C5a" of the complement system arise through proteolytic cleavage from the inactive precursors C3 and C5, respectively. When activated, they attract macrophages and neutrophil granulocytes . These phagocytes have TLR-type receptors on their surface. The TLRs react to bacterial proteoglycans or lipopolysaccharides (LPS), DNA and RNA. They trigger a signal cascade in their carrier cells that ultimately stimulates the defense against infection. After recognition of these bacterial surface structures on the extracellular side, intracellular signal cascades are triggered by TLR.

The recognition of PAMPs (Pathogen Associated Molecular Patterns) by TLRs leads to an increase in the transcription rate of certain genes, depending on which TLRs and which cell types are involved. The difference between the signal cascades activated by the individual TLRs can be explained at least in part by the TIR domain-containing adapter molecules (TIR domain-containing adapter molecules). There are five TIR domain-containing adapter molecules, including MyD88, TRIF / TICAM-1 (TIR-domain-containing adapter inducing IFN-β), TIRAP / Mal, TRAM (TRIF-related adapter molecule), and SARM (sterile alpha and Armadillo motif-containing protein). TLR signal chains are roughly divided into two different reaction chains depending on the involvement of the adapter molecules MyD88 and TRIF.

This leads to phosphorylation and thus activation of intracellular kinases , the task of which is the phosphorylation of intracellular inhibitors of transcription factors . First, the adapter protein MyD88 binds to the cytoplasmic section of the TLR. As a result, the IL-1 receptor-associated kinase (IRAK) now binds to MyD88 and activates itself through autophosphorylation. After further individual steps, the transcription factor NF-κB is activated , which then translocates into the cell nucleus and expresses it there Regulates genes for TNFα, IL-1, IL-12 and E-selectin.

literature

Individual evidence

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