|Toll-like receptor 11|
Toll-like receptor 11 (TLR11) is a protein that in mice and rats is encoded by the gene TLR11, whereas in humans it is represented by a pseudogene. TLR11 belongs to the toll-like receptor (TLR) family and the interleukin-1 receptor/toll-like receptor superfamily. In mice, TLR11 has been shown to recognise (bacterial) flagellin and (eukaryotic) profilin present on certain microbes, it helps propagate a host immune response. TLR11 plays a fundamental role in both the innate and adaptive immune responses, through the activation of Tumor necrosis factor-alpha,the Interleukin 12 (IL-12) response, and Interferon-gamma (IFN-gamma) secretion. TLR11 mounts an immune response to multiple microbes, including Toxoplasma gondii (T. gondii), Salmonella species, and uropathogenic E. coli, and likely many other species due to the highly conserved nature of flagellin and profilin.
Proteins in the TLR family are pattern recognition receptors whose task is to alert the immune system of foreign invaders. These foreign invaders may be bacteria, viruses, fungi, or parasites. Every TLR has three domains that compose its overall structure: a leucine-rich repeat (LRR) region, a transmembrane domain, and a Toll/Interleukin-1 receptor (TIR) domain. The LRR region of TLR11 interacts with the T. gondii profilin and uropathogenic E. coli. It is localized to the endosomal compartment of the cell with the LRR region facing into the endosome.The domain mounts TLR11 to the endosomal membrane and connects the LRR region to the TIR domain. Lastly, the TIR domain resides on the cytosolic side of the cell. Its job is to initiate a signal that will activate the Toll pathway in the cell. The ultimate end of the Toll pathway is the expression of genes by the transcription factors NF-κB and AP-1 that initiate an immune response to the pathogen.
TLR11 is expressed in macrophages, dendritic cells, and liver, kidney, and bladder epithelial cells.
Many mammals, including humans, have the TLR11 gene. But only some species’ TLR11 can successfully code for the functional protein that is able to play an active role in the innate immune response. Human TLR11 contains stop codons, meaning functional TLR11 protein is not found in humans.All the collective knowledge about the function and immunopathology of TLR11 has come from experiments in other animals, often mice.
Experiments on mouse TLR11 both in vivo and in vitro have revealed much about the biological role of TLR11. TLR11 has a primary role as a "sentinel" for the innate immune system. Like all TLRs, TLR11 distinguishes between self molecules and non-self molecules. When an infection of T. gondii or uropathogenic E. coli reaches a host cell expressing TLR11 on its surface, the LRR region binds to the pathogen and activates the Toll pathway through the TIR domain. The transcription factor NF-kappa B at the end of the pathway transcribes pro-inflammatory cytokines (such as IL-12) and chemokines. Activation of the Toll pathway also results in the expression of co-stimulatory molecules on dendritic cells, which then go on to activate naïve CD4 cells in the lymph nodes.
T. gondii is an apicomplexan parasite that can cause infection in humans. The parasite can live in many mammals and birds, but it carries out the sexual part of its lifecycle in cats. Feline feces from infected cats or undercooked meat from infected livestock contain T. gondii oocysts. Ingesting these could lead to Toxoplasmosis, a disease which at its worst can cause encephalitis or miscarriage as the disease is passed from mother to fetus.
T. gondii and other apicomplexan parasites rely on actin-dependent gliding motility in order to gain access to the body. This form of cellular motion requires profilin, an actin filament binding protein that helps restructure the actin cytoskeleton. Without profilin, T. gondii can still grow and replicate, but it loses the ability to pass through cell layers and biological barriers in order to carry out infection. Thus profilin is a conserved, essential protein for T. gondii infection efficacy.
Profilin from T. gondii is a critical parasite ligand for TLR11. It preferentially induces IL-12 production in dendritic cells that communicate with natural killer cells and cytotoxic T cells. In one study, mice bred to not express TLR11 (knock-out mice) did not mount the IL-12 response upon profilin stimulation. Dendritic cells in the knock-out mice also failed to migrate to lymph nodes, halting the initiation of the adaptive immune response.
Furthermore, mice lacking the TLR11 gene are susceptible to pancreatitis, fat cell necrosis, and increased inflammatory reactants. Pancreatitis is also a pathological response in humans to T. gondii infection.Wild-type mice are able to produce an immune response, marked by IL-12 and IFN-gamma production that is unseen in humans, who lack a functional TLR11 protein.
Uropathogenic E. coli is a bacterium that causes urinary tract infections. The infection begins with colonization in the urethra. The infection typically ascends and can reside primarily in the bladder or the kidneys, though the latter is more threatening due to the possibility of transmission of pathogens to the bloodstream.
TLR11 is expressed in mouse kidney and bladder epithelial cells, the cells that line the urinary tract and protect the underlying tissue. In another study of TLR11 in mice, exposure of human uropathogenic E. coli bacteria to mouse cells expressing TLR11 resulted in NF-kappa B activation. While the bladders from both wild-type and knockout mice were almost equally infected, the kidneys of the mice without TLR11 had 10,000 times more bacteria and showed a greater inflammatory response than the normal mouse kidneys. TLR11 appears to recognize a pattern on uropathogenic E. coli and can prevent ascending infection.
It is important to note that mice as a species do not grapple with urinary tract infections like humans do unless some part of their TLR11 immune response is made non-functional. With functional TLR11, humans might not succumb to urinary tract infections so readily.
Flagellin is a globular protein that arranges itself in a hollow cylinder to form the filament in a bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons. Flagellin is the principal component of bacterial flagellum, and is present in large amounts on nearly all flagellated bacteria.
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the last three are not found in humans, and there isn't a functional gene for TLR10 in mice. TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.
Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast array of different types of molecules can serve as PAMPs, including glycans and glycoconjugates.
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.
IRAK-4, in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 is important for its clinical applications.
Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene.
An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282. TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.
In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."
Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.
Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.
Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to an pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 preferentially binds DNA present in bacteria and viruses, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.
Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.
A non-specific immune cell is an immune cell that responds to many antigens, not just one antigen. Non-specific immune cells function in the first line of defense against infection or injury. The innate immune system is always present at the site of infection and ready to fight the bacteria; it can also be referred to as the "natural" immune system. The cells of the innate immune system do not have specific responses and respond to each foreign invader using the same mechanism.
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of Gasdermin-D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. In the case of dysregulation of inflammasome activation, an assortment of major diseases, such as cancer, autoimmune, metabolic and neurodegenerative diseases may arise.
The Toll/interleukin-1 receptor (TIR) homology domain is an intracellular signaling domain found in MyD88, SARM1, interleukin-1 receptors, Toll receptors and many plant R proteins. It contains three highly conserved regions, and mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. TIR-like motifs are also found in plant proteins where they are involved in resistance to disease and in bacteria where they are associated with virulence. When activated, TIR domains recruit cytoplasmic adaptor proteins MyD88 (UniProt NAD+ cleavage activity, such as in SARM1. In the case of SARM1, the TIR NADase activity leads to the production of Nam, ADPR and cADPR and the activation of downstream pathways involved in Wallerian degeneration and neuron death.) and TOLLIP (Toll interacting protein, UniProt ). In turn, these associate with various kinases to set off signaling cascades. Some TIR domains have also been found to have intrinsic
The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.