Toll-like receptor 11

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Toll-like receptor 11
Identifiers
Organism Mus Musculus
SymbolTLR11
UniProt Q6R5P0
Search for
Structures Swiss-model
Domains InterPro

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, [1] the interleukin 12 (IL-12) response, [2] and interferon-gamma (IFN-gamma) secretion. [3] TLR11 mounts an immune response to multiple microbes, including Toxoplasma gondii (T. gondii), Salmonella species, [4] and uropathogenic E. coli, and likely many other species due to the highly conserved nature of flagellin and profilin. [5] [6]

Contents

Leucine-rich repeat PDB 2bnh EBI.jpg
Leucine-rich repeat

Structure and localization

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. [7] 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. [8]

Function

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. [9] All the collective knowledge about the function and immunopathology of TLR11 has come from experiments in other animals, often mice. [10]

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. [11]

Toxoplasma gondii Toxoplasma gondii tachy.jpg
Toxoplasma gondii

TLR11 and T. gondii

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. [12]

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. [2]

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. [3] 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.

TLR11 and uropathogenic E. coli

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. [1]

Related Research Articles

Flagellins are a family of proteins present in flagellated bacteria which arrange themselves in a hollow cylinder to form the filament in a bacterial flagellum. Flagellin has a mass on average of about 40,000 daltons. Flagellins are the principal component of bacterial flagella that have a crucial role in bacterial motility.

<span class="mw-page-title-main">Toll-like receptor</span> Class of immune system proteins

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-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 reached 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. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

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, as well as by 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.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">IRAK4</span> Protein-coding gene in humans

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, IRAK3 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 has important 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.

<span class="mw-page-title-main">MYD88</span> Protein found in humans

Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene. originally discovered in the laboratory of Dan A. Liebermann as a Myeloid differentiation primary response gene.

<span class="mw-page-title-main">Alveolar macrophage</span> Macrophage found in the lungs

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.

<span class="mw-page-title-main">Toll-like receptor 2</span> Cell surface receptor found in humans

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."

<span class="mw-page-title-main">Toll-like receptor 1</span> Cell surface receptor found in humans

Toll-like receptor 1 (TLR1) is a member of the toll-like receptor (TLR) family of pattern recognition receptors (PRRs) that form the cornerstone of the innate immune system. TLR1 recognizes bacterial lipoproteins and glycolipids in complex with TLR2. TLR1 is a cell surface receptor. In humans, TLR1 is encoded by the TLR1 gene, which is located on chromosome 4.

<span class="mw-page-title-main">Toll-like receptor 7</span> Protein found in humans

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.

<span class="mw-page-title-main">Toll-like receptor 5</span> Protein found in humans

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, including Inflammatory bowel disease due to the high expression of TLR in intestinal lamina propria dendritic cells. 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.

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">Toll-like receptor 6</span> Protein found in humans

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 a pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.

<span class="mw-page-title-main">Toll-like receptor 9</span> Protein found in humans

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 is expressed on endosomes internalized from the plasma membrane, binds DNA, 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.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

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.

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.

Jonathan C. Kagan is an American immunologist and the Marian R. Neutra, Ph.D. Professor of Pediatrics at Harvard Medical School. He is also the director of Basic Research and Shwachman Chair in Gastroenterology at Boston Children's Hospital. Kagan is a world leader in defining the molecular basis of innate immunity and inflammation.

References

  1. 1 2 Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (March 2004). "A toll-like receptor that prevents infection by uropathogenic bacteria". Science. 303 (5663): 1522–6. Bibcode:2004Sci...303.1522Z. doi:10.1126/science.1094351. PMID   15001781. S2CID   31175981.
  2. 1 2 Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al. (June 2005). "TLR11 activation of dendritic cells by a protozoan profilin-like protein". Science. 308 (5728): 1626–9. Bibcode:2005Sci...308.1626Y. doi: 10.1126/science.1109893 . PMID   15860593. S2CID   34165967.
  3. 1 2 Yarovinsky F, Hieny S, Sher A (December 2008). "Recognition of Toxoplasma gondii by TLR11 prevents parasite-induced immunopathology". Journal of Immunology. 181 (12): 8478–84. doi:10.4049/jimmunol.181.12.8478. PMC   4809201 . PMID   19050265.
  4. ↑ Mathur R, Oh H, Zhang D, Park SG, Seo J, Koblansky A, et al. (October 2012). "A mouse model of Salmonella typhi infection". Cell. 151 (3): 590–602. doi:10.1016/j.cell.2012.08.042. PMC   3500584 . PMID   23101627.
  5. ↑ Bird L (2005). "Innate immunity: A new ligand for TLR11". Nature Reviews Immunology. 5 (6): 432. doi: 10.1038/nri1638 .
  6. ↑ Hatai H, Lepelley A, Zeng W, Hayden MS, Ghosh S (2016). "Toll-Like Receptor 11 (TLR11) Interacts with Flagellin and Profilin through Disparate Mechanisms". PLOS ONE. 11 (2): e0148987. doi: 10.1371/journal.pone.0148987 . PMC   4747465 . PMID   26859749.
  7. ↑ Pifer R, Benson A, Sturge CR, Yarovinsky F (February 2011). "UNC93B1 is essential for TLR11 activation and IL-12-dependent host resistance to Toxoplasma gondii". The Journal of Biological Chemistry. 286 (5): 3307–14. doi: 10.1074/jbc.M110.171025 . PMC   3030336 . PMID   21097503.
  8. ↑ Lauw FN, Caffrey DR, Golenbock DT (October 2005). "Of mice and man: TLR11 (finally) finds profilin". Trends in Immunology. 26 (10): 509–11. doi:10.1016/j.it.2005.08.006. PMID   16111920.
  9. ↑ Ishii KJ, Koyama S, Nakagawa A, Coban C, Akira S (June 2008). "Host innate immune receptors and beyond: making sense of microbial infections". Cell Host & Microbe. 3 (6): 352–63. doi: 10.1016/j.chom.2008.05.003 . PMID   18541212.
  10. ↑ Atmaca HT, Kul O, Karakuş E, Terzi OS, Canpolat S, Anteplioğlu T (June 2014). "Astrocytes, microglia/macrophages, and neurons expressing Toll-like receptor 11 contribute to innate immunity against encephalitic Toxoplasma gondii infection". Neuroscience. 269: 184–91. doi:10.1016/j.neuroscience.2014.03.049. PMID   24704432. S2CID   6717043.
  11. ↑ Janeway CA, Travers P, Walport M, Shlomchik MJ (2001). "The production of armed effector T cells". Immunobiology (5th ed.). New York: Garland Science. ISBN   0-8153-3642-X.
  12. ↑ Plattner F, Yarovinsky F, Romero S, Didry D, Carlier MF, Sher A, Soldati-Favre D (February 2008). "Toxoplasma profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response". Cell Host & Microbe. 3 (2): 77–87. doi: 10.1016/j.chom.2008.01.001 . PMID   18312842.
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