Calprotectin

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Calprotectin is a complex of the mammalian proteins S100A8 and S100A9. [1] [2] Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen. [2] [3] The proteins exist as homodimers but preferentially exist as S100A8/A9 heterodimers or heterotetramers (calprotectin) with antimicrobial, proinflammatory and prothrombotic properties. [4] [5] In the presence of calcium, calprotectin is capable of sequestering the transition metals iron, [6] manganese and zinc [2] [7] via chelation. [8] This metal sequestration affords the complex antimicrobial properties. [2] [7] Calprotectin is the only known antimicrobial manganese sequestration protein complex. [9] Calprotectin comprises as much as 60% of the soluble protein content of the cytosol of a neutrophil, [2] [10] [11] and it is secreted by an unknown mechanism during inflammation. [3] Faecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases. [10] [12] Blood-based calprotectin (in serum and plasma) is used in diagnostics of multiple inflammatory diseases, including autoimmune diseases, like arthritis, and severe infections including sepsis. [13] [14]

Contents

Structure

Crystal structure of Mn and Ca loaded calprotectin, showing two S100A8-S100A9 dimers. The grey and blue chains represent S100A8 and S100A9, respectively. Purple spheres represent Mn and green spheres represent Ca . Only one manganese ion can bind per calprotectin dimer. Calprotectin-4GGF.png
Crystal structure of Mn and Ca loaded calprotectin, showing two S100A8-S100A9 dimers. The grey and blue chains represent S100A8 and S100A9, respectively. Purple spheres represent Mn and green spheres represent Ca . Only one manganese ion can bind per calprotectin dimer.

The human homologue of calprotectin is a 24  kDa dimer, [9] and is formed by the protein monomers S100A8 (10,835 Da) and S100A9 (13,242 Da). [4] [5] The primary structure of calprotectin can vary between species. For instance, the mouse homologue of S100A8 is 10,295 Da, [15] while the S100A9 homologue is 13,049 Da. [16] Early size exclusion chromatography experiments incorrectly indicated that calprotectin had a molecular mass of 36.5 kDa; [2] [11] occasionally this value is used in contemporary literature. Calprotectin S100A8-S100A9 dimers can non-covalently pair with one another to form 48 kDa tetramers.

Metal binding

Calprotectin has a high affinity for calcium, zinc, iron, and manganese. [10] [11] [17] [6] Each of S100A8 and S100A9 contain two EF-hand type Ca2+ binding sites, [9] [3] and calprotectin is able to bind a total of four calcium ions per dimer or eight calcium ions per tetramer. [18] Calcium binding induces a conformational change in the complex that improves its affinity for transition metals, and promotes tetramer formation. [2] [9] A maximum of two transition metal ions may bind to each calprotectin S100A8-S100A9 dimer. [9]

A calprotectin dimer can bind only one manganese or iron ion with high affinity, and it can do this only in the presence of calcium. [9] [19] [6] Zinc can bind at two sites within the calprotectin dimer, and this can occur in the absence of calcium. [2] Calcium, however, improves calprotectin's affinity for zinc. [9] While calprotectin metal binding occurs at the interface of S100A9 and S100A8 monomers, the independent monomers have some capacity for zinc binding, and may contribute to zinc homeostasis within mammals. [2] [4] [5]

His6 coordination of Mn in calprotectin. S100A8 histidine residues are coloured grey, S100A9 histidine residues are coloured purple. Mn Centre Calprotectin-4GGF.pdf
His6 coordination of Mn in calprotectin. S100A8 histidine residues are coloured grey, S100A9 histidine residues are coloured purple.

The first of the two calprotectin metal binding sites consists of a His3Asp motif, with S100A8 contributing two histidine ligands (His83 and His87), and S100A9 contributing a histidine and an aspartic acid ligand (His20 and Asp30). [9] The second site can coordinate metals through a tetra-histidine (His4) or a hexa-histidine (His6) binding motif. In the case of His4 binding, S100A8 coordinates through both His17 and His27 while S100A9 coordinates through His91 and His95. [9] In hexa-histidine binding two further histidine residues, His103 and His105, are recruited from the C-terminal end of S100A9 to enable octahedral coordination of the transition metal. [9] Manganese or iron are bound by the calprotectin dimer at this His6 site. [9] [6] Zinc can be bound to either of the sites that form at the interface between S100A8 and S100A9 monomers. [9] [19]

Inflammatory disease

Calprotectin constitutes up to 60% of soluble protein content in the cytosol of neutrophil granulocytes, [2] [10] [11] and it can be found at a lower concentration in monocytes, macrophages, and squamous epithelial cells. [2] [10] [11] Calprotectin enters into pus and abscess fluid during neutrophil cell death, along with other antimicrobial proteins. [2]

Mammalian cells secrete calprotectin during the inflammatory response. Circulating activated platelets and platelet-leukocyte aggregates are increased in acute and chronic sterile thrombo-inflammatory diseases. Plasma calprotectin is elevated in persons with metabolic syndrome, a disease characterized by chronic inflammation. [20] Calprotectin is secreted in the mouth during inflammation of the gingiva and during oral candidiasis infection. [21] [22] People who have mutations in the calprotectin gene appear susceptible to serious gum infections. [21] Manganese sequestration by calprotectin is likely important during lung inflammation. [7] The exact mechanism by which S100A8 and S100A9 is secreted by mammalian cells during inflammation remains unknown. [3] In lung autopsies from patients with inflammation caused by COVID-19, heterodimeric S100A8/A9 is mainly detected in neutrophils and deposited on vessel walls. [23] Platelet glycoprotein Ib alpha (GP1BA;GPIbα) is the receptor for S100A8/A9 on platelets. [23] In vitro, platelets adhere to and partially spread on S100A8/A9, leading to the formation of distinct populations of P-selectin+ and phosphatidylserine+ platelets. The prothrombotic pathway initiated by interaction of S100A8/A9 with GPIbα induces the formation of procoagulant platelets and fibrin (CD36 has a supporting role). [23]

Antimicrobial properties

Transition metals are essential to the survival of all organisms. [24] Mammals strictly limit metal availability as a part of the innate immune system, and this helps prevent infection by microbes and fungi. [24] Calprotectin was first described in the 1980s as a mammalian antimicrobial protein that acts through the sequestration of zinc. [1] [2] [9] It is now known that calprotectin also has antibacterial and antifungal properties that arise from its ability to sequester manganese and iron. [7] [9] [6] Calprotectin is the only known antimicrobial agent that acts through manganese sequestration. [9]

Faecal calprotectin

Calprotectin becomes available in the intestinal lumen via leukocyte shedding, [1] active secretion, [2] [11] cell disturbance, and cell death. [1] [11] This results in elevated faecal calprotectin levels, which can be detected in the stool. [1] [11] Elevated faecal calprotectin levels therefore indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation. [1] [11] [17] As people with active inflammatory bowel diseases (IBD) such as ulcerative colitis or Crohn disease have as much as a 10-fold increase in faecal calprotectin levels, [10] the measurement of faecal calprotectin can serve as a biochemical test for these diseases.

Although a relatively new test, faecal calprotectin is regularly used as an indicator for IBD during treatment and as a diagnostic marker. [12] Faecal calprotectin tests can also function in distinguishing patients with irritable bowel syndrome from those with IBD. [1] [11] Calprotectin is useful as a marker, as it is resistant to enzymatic degradation, and can be easily measured in faeces. [25] Although faecal calprotectin correlates significantly with disease activity in people with confirmed IBD, [26] elevated faecal calprotectin can be a false-positive indicator of IBD under some conditions. Importantly, intake of proton pump inhibitor is associated with significantly elevated calprotectin values. [27] Furthermore, positive faecal calprotectin does not help in localizing IBD, or in distinguishing ulcerative colitis from Crohn's disease. [1] Faecal calprotectin can also indicate other gastrointestinal conditions such as colorectal cancer, gastroenteritis, and food intolerance. [1] Calprotectin levels vary depending on age, comorbidity, and may vary day-to-day within individuals. [1] Faecal calprotectin could be used as a preliminary screen in otherwise functional patients suspected of having IBD, or as a means of following mucosal healing. [1] In patients with SARS-CoV-2 infection, elevated faecal calprotectin has been demonstrated to correlated with COVID-19 induced thrombosis even in patients without gastrointestinal symptoms. [28] The potential for using faecal calprotectin in this way is debated, however, and cut-off levels have not been agreed upon. [1]

See also

Related Research Articles

<span class="mw-page-title-main">Crohn's disease</span> Type of inflammatory bowel disease

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.

<span class="mw-page-title-main">Ulcerative colitis</span> Inflammatory bowel disease that causes ulcers in the colon

Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and anemia may also occur. Often, symptoms come on slowly and can range from mild to severe. Symptoms typically occur intermittently with periods of no symptoms between flares. Complications may include abnormal dilation of the colon (megacolon), inflammation of the eye, joints, or liver, and colon cancer.

<span class="mw-page-title-main">Inflammatory bowel disease</span> Medical condition

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine, as well as the mouth, esophagus, stomach and the anus, whereas UC primarily affects the colon and the rectum.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in humans

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<span class="mw-page-title-main">P-selectin</span> Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

<span class="mw-page-title-main">S100 protein</span> Family of vertebrate proteins involved in cell division and inflammation

The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are encoded by a family of genes whose symbols use the S100 prefix, for example, S100A1, S100A2, S100A3. They are also considered as damage-associated molecular pattern molecules (DAMPs), and knockdown of aryl hydrocarbon receptor downregulates the expression of S100 proteins in THP-1 cells.

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

RAGE, also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively, and by active secretion from macrophages, natural killer cells, and dendritic cells.

<span class="mw-page-title-main">Calgranulin</span> Protein

Calgranulin is an S100 calcium-binding protein that is expressed in multiple cell types, including renal epithelial cells and neutrophils.

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

Neutrophil elastase is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Neutrophil elastase is secreted by neutrophils during inflammation, and destroys bacteria and host tissue. It also localizes to neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.

Bactericidal permeability-increasing protein (BPI) is a 456-residue (~50kDa) protein that is part of the innate immune system, coded for in the human by the BPI gene. It belongs to the family of lipid-binding serum glycoproteins.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">Neutrophil extracellular traps</span> Networks of fibres which bind pathogens

Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. Neutrophils are the immune system's first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro activation with the pharmacological agent phorbol myristate acetate (PMA), Interleukin 8 (IL-8) or lipopolysaccharide (LPS), neutrophils release granule proteins and chromatin to form an extracellular fibril matrix known as NET through an active process.

<span class="mw-page-title-main">Proteinase-activated receptor 1</span> Mammalian protein found in humans

Proteinase-activated receptor 1 (PAR1) also known as protease-activated receptor 1, coagulation factor II receptor and thrombin receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

<span class="mw-page-title-main">S100A8</span> Protein-coding gene in Homo sapiens

S100 calcium-binding protein A8 (S100A8) is a protein that in humans is encoded by the S100A8 gene. It is also known as calgranulin A.

<span class="mw-page-title-main">S100A9</span> Protein-coding gene in the species Homo sapiens

S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene.

Faecal calprotectin is a biochemical measurement of the protein calprotectin in the stool. Elevated faecal calprotectin indicates the migration of neutrophils to the intestinal mucosa, which occurs during intestinal inflammation, including inflammation caused by inflammatory bowel disease. Under a specific clinical scenario, the test may eliminate the need for invasive colonoscopy or radio-labelled white cell scanning.

<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

<span class="mw-page-title-main">Segmental colitis associated with diverticulosis</span> Medical condition

Segmental colitis associated with diverticulosis (SCAD) is a condition characterized by localized inflammation in the colon, which spares the rectum and is associated with multiple sac-like protrusions or pouches in the wall of the colon (diverticulosis). Unlike diverticulitis, SCAD involves inflammation of the colon between diverticula, while sparing the diverticular orifices. SCAD may lead to abdominal pain, especially in the left lower quadrant, intermittent rectal bleeding and chronic diarrhea.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

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