Interleukin-17 receptor (IL-17R) is a

cytokine receptor Cytokine receptors are receptors that bind to cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly bec ...

which belongs to new subfamily of receptors binding proinflammatory cytokine interleukin 17A, a member of IL-17 family ligands produced by T helper 17 cells (Th17). IL-17R family consists of 5 members: IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE. Functional IL-17R is a transmembrane receptor complex usually consisting of one IL-17RA, which is a founding member of the family, and second other family subunit, thus forming heteromeric receptor binding different ligands. IL-17A, a founding member of IL-17 ligand family binds to heteromeric IL-17RA/RC receptor complex. IL-17RB binds preferentially IL-17B and IL-17E and heteromeric IL-17RA/RE complex binds IL-17C. However, there is still unknown ligand for IL-17RD. The first identified member IL-17RA is located on human chromosome 22, whereas other subunits IL-17RB to IL-17RD are encoded within human chromosome 3.

Evolution

IL17RD is probably the most ancient member of IL-17 receptor family. It was firstly identified in

zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...

and its homologues were also found in sea lamprey and ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...

''. There are two IL-17Rs (IL-17RA and IL-17RD) in the genome of the basal chordate ''

Amphioxus The lancelets ( or ), also known as amphioxi (singular: amphioxus ), consist of some 30 to 35 species of "fish-like" benthic filter feeding chordates in the order Amphioxiformes. They are the modern representatives of the subphylum Cephalochorda ...

''. After two rounds of whole genome duplications, these two IL-17R genes expanded into five early vertebrate IL-17R genes, IL-17RA to IL-17RE. Two (IL-17RA and IL-17RD) are found in most vertebrates, whereas the other three (IL-17RB, IL-17RC and IL-17RE) have undergone some losses in vertebrates during evolution.

Structure

Structure of IL-17 receptors is unique in comparison with all other known receptor families. IL-17RA is by far the largest member of the family and has the longest cytoplasmic tail of the family. This cytoplasmic tail provides docking sites for numerous signaling intermediates. However, conformational changes mediated after ligand binding are essential for association of these signaling molecules as well as the second receptor subunit and enable subsequent signal transduction. IL-17RA/RC receptor complex is composed of both

alpha helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

and

beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a g ...

s and its extracellular part contains two

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

domains, which are involved in formation of two ligand binding sites. Intracellular part of IL-17 receptors consists of several structural domains including SEFIR motif, a highly conserved motif within IL-17R family. Although SEFIR motif also serves as signaling molecule in

IL-1R Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections ...

Toll-like receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...

families, its signaling features and associated adaptor molecules are quite different in IL-17 receptor family. In case of IL-17RA, it has a longer cytoplasmic tail which contains some additional structural domains, such as TILL domain ("TIR-like loop") or inhibitory CBAD domain (" C/EBPβ-activation domain").

Expression and regulation

IL-17RA has been observed at high levels in various tissues such as haematopoietic, bone marrow, thymus, and spleen tissue. IL-17RA is also normally found at low levels in colon, small intestine, and lung tissues. IL-17RA is expressed in CD8+ T cells, and upregulated by IL-15 and IL-21. IL-17RA may be internalised after binding IL-17A. IL-17RB is highly expressed in the kidney, liver and Th2 cells and its overexpression promotes triggering of Th2 immune response. IL-17RC expression is low in haematopoietic tissues and high in non-immune cells of the prostate, liver, kidney, thyroid and joints. Another family subunit IL-17RE is highly expressed in Th17 cells.

Function

Signaling via IL-17R protects our body against several bacterial and

fungal A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from th ...

infections caused by invading pathogens, especially against ''

Candida albicans ''Candida albicans'' is an opportunistic pathogenic yeast that is a common member of the human gut flora. It can also survive outside the human body. It is detected in the gastrointestinal tract and mouth in 40–60% of healthy adults. It is us ...

''. Binding of proinflammatory cytokin IL-17A to IL-17 receptor causes important conformational changes that enable binding of signaling adaptors, such as Act1 or TRAF proteins. Binding of these signaling adaptors triggers activation of several signaling pathways, including

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

, pathways of MAPKs (mitogen-activated protein kinases) or C/EBPs pathway. Activation of these pathways results in expression and production of inflammatory cytokines such as

TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

or IL-1β, chemokines, which drive infiltration of

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s and antimicrobial products, for example

defensin Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, ...

s and

mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most ...

s. All these products contribute to the development of inflammation and elimination of various foreign pathogens. Patients with impaired IL-17R signaling suffer from yeast infections, such as CMC (chronic mucocutaneous candidiasis), or respiratory infections. Apart from production of these inflammatory products ''de novo'', signaling via IL-17R also promotes stabilization of already existent specific mRNA transcripts. This stabilization prolongs the half-life of mRNAs and prevents their quick degradation. Again, these mRNA transcripts predominantly encode proinflammatory cytokines or chemokines.

Pathology

Although IL-17R provides crucial protection against a variety of microbial infections in humans, it must be very strictly regulated. Immoderate and undue activation of IL-17R by IL-17A results in development of several autoimmune diseases, specifically

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

Clinical significance

These days, several

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

neutralizing IL-17A have potential for the treatment of autoimmune diseases in humans, such as plaque psoriasis. Majority of these monoclonal antibodies are humanized IgG1. This therapy may also be soon used for protection against

periodontal Periodontology or periodontics (from Ancient Greek , – 'around'; and , – 'tooth', genitive , ) is the specialty of dentistry that studies supporting structures of teeth, as well as diseases and conditions that affect them. The supporting ...

bone loss as it is currently being tested in mice. IL-17RA has been observed at high levels in people undergoing treatment for cardiac fibroblasts and in certain tissues such as: haematopoietic, bone marrow, thymus, and spleen tissue.

As therapy targets

Approved anti-IL-17(R) drugs include:

Brodalumab Brodalumab, sold under the brand name Siliq in the US and Kyntheum in the EU, is a human monoclonal antibody designed for the treatment of inflammatory diseases. In February 2017, it received US FDA approval to treat moderate to severe plaque p ...

(Siliq), an antibody targeting IL-17 receptor is approved for the treatment of psoriasis.

Ixekizumab Ixekizumab, sold under the brand name Taltz, is an injectable medication for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody. The substance acts by binding interleukin 17A and neutralizing it, re ...

and

secukinumab Secukinumab, sold under the brand name Cosentyx, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis ...

approved for plaque psoriasis are antibodies which target IL-17A itself rather than the receptor.

References

External links

* * 'http://www.rcsb.org/pdb/explore/explore.do?structureId=3JVF' {{Interleukin receptor modulators IL17 family cytokine receptors