Introduction to Inflammation Markers

Kristina Whitfield

Nov 21, 2019

Science 2

Inflammation is the body’s response to pathogens. Its function is to eliminate the initial causes of cell damage and to initiate tissue repair. Learn more about the different markers in response to the inflammation and how they are use in diagnosis and prognosis.

Author: Kristina Whitfield Undertakes marketing activities for Pivotal Scientific and their clients.

Kristina Whitfield

Inflammation is the body’s generic response to pathogens, irritants, or damaged cells, and it is considered a hallmark of the innate immune response. Its function is to eliminate the initial causes of cell damage, to remove necrotic cells and tissues and to initiate tissue repair.  The classical signs of acute inflammation are heat, pain, redness and swelling caused by the release of molecular signalling products resulting in dilated vasculature. The increased supply of neutrophils and macrophages assist in the process. Subdued inflammation could lead to progressive tissue destruction caused by the harmful stimulus. Persistent, chronic inflammation leads to a shift in cell types such as mononuclear cells at the inflammation site. This may lead to diseases such as allergies, atherosclerosis, cancer, neurodegenerative or autoimmune diseases. Inflammation is therefore closely regulated by the body.

As a response to inflammation, IL6 triggers the increase of the so-called Acute Phase protein levels in the circulatory system, such as CRP, SAA and AAT. PCT levels indicate bacterial or viral origin of inflammation, while faecal Calprotectin is commonly used to diagnose intestinal inflammations. NGAL is commonly known as a renal injury marker, but IL8 is a more generic inflammation marker. Finally, Trypsonogen-2 levels are monitored to detect acute pancreatitis and its severity.

C-Reactive Protein (CRP)

CRP is secreted in response to a variety of inflammatory cytokines, and its main biological role is the activation of the complement system and other proinflammatory processes. Its binding capacity to molecules like phosphocholine, widely distributed in cellular membranes and in polysaccharides of pathogens, makes CRP recognize a range of pathogenic targets as well as membranes of damaged and dying host cells. Therefore, this marker is a widely used indicator of either infection or inflammatory conditions.

Serum Amyloid A (SAA)

Like CRP, also levels of the SAA proteins increase within hours in response to inflammatory signals as part of the acute phase response.  Both SAA1 and SAA2 expression is regulated by proinflammatory cytokines IL1, IL6 and TNF-alpha. The significance of chronic inflammation in the development and progression of many other severe diseases, such as various cancers and cardiovascular diseases, suggests SAA might be a useful prognostic marker. The proteins are highly conserved across species throughout vertebrates and invertebrates.

Calprotectin

Calprotectin is secreted by neutrophils at the site of inflammation. It is a calcium binding heterodimer existing of S100A8 and S100A9 monomers with the capacity to bind to metals such as manganese or zinc. These properties give Calprotectin antimicrobial activity. Calprotectin levels in plasma are substantially increased in infectious or inflammatory conditions. Elevated faecal calprotectin levels indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation. Analysis of faecal calprotectin is commonly used to diagnose intestinal inflammations, especially inflammatory bowel disease (IBD). Information about faecal calprotectin levels provides valuable support for treatment decisions as it can differentiate IBD from irritable bowel syndrome.

Procalcitonin (PCT)

PCT is the precursor for Calcitonin and Katacalcin, both hormones lower calcium levels in the blood.  The remaining propeptide, left after maturation, is the N-terminal PCT with unknown function. The serum PCT levels are normally below detection, but increase upon inflammatory cues from bacterial infection. However, the levels remain low when these cues are from viral or non-infectious origin. Thus, PCT serves as a marker to decide if antibiotics are required, especially when sepsis is suspected.

Neutrophil gelatinase-associated lipocalin (NGAL)

Neutrophil gelatinase-associated lipocalin (a.k.a. Lipocalin-2) is a small glycoprotein involved in innate immunity by limiting bacterial growth in epithelial tissues. Elevated levels of blood and urine NGAL are associated with acute or chronic renal failure, and elevated serum levels indicate active inflammatory bowel disease (IBD) and cardiovascular events.

Alpha-1 Antitrypsin (AAT)

AAT is a member of the Serine Protease Inhibitors (Serpins) and it is in relative high abundance in blood (1.5-3.5g/l). It protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and its levels increase manifold upon acute inflammation. In its absence (AAT deficiency), elastase is free to break down elastin, which contributes to the elasticity of the lungs. This results in respiratory complications such as emphysema, or COPD in adults and cirrhosis in adults and children.

Interleukin 6 (IL6)

IL6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. T cells and macrophages secrete IL6 to stimulate immune response to trauma, especially burns or other tissue damage leading to inflammation. IL6 is an important mediator of increased temperature both locally (inflammation site) and on the entire body upon infection (fever). IL-6 is responsible for stimulating acute phase protein synthesis (such as CRP, SAA and AAT), as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and it is antagonistic to regulatory T cells. Its role in a large variety of diseases, including autoimmunity and cancer, has led to clinical applications both as a marker (for example in advanced/metastatic cancer patients) and as a therapeutic target (already FDA-approved anti-IL6 therapy for Rheumatoid Arthritis).

Interleukin 8 (IL8)

IL8 is an interleukin produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells as an important mediator of the innate immune response. It serves as a chemical signal that attracts neutrophils and other granulocytes at the site of inflammation. Its levels increase as a response to inflammation-associated oxidative stress and therefore IL8 serves as generic inflammation marker.

IL-8 is also known to be a potent promoter of angiogenesis. Moreover, It is implicated in the pathogenesis of a common respiratory tract disease caused by viral infection called bronchiolitis. Raised IL8 levels are associated with many pathologies and would usually serve as a first indicator for further diagnostic tests.

Trypsinogen-2

Trypsinogens are the precursor forms of the pancreatic trypsins. Although there are three genes encoding for the three trypsin precursors, their homology among each other is so high that they are indistinct in detection by most antibodies. Trypsinogens are activated by enteropeptidase in the intestinal mucosa to form trypsin. Once activated, the trypsin can activate more trypsinogen to digest any protein by cleaving peptide bonds. High serum trypsinogen levels are seen with acute pancreatitis, and with cystic fibrosis.  Determination of urine trypsinogen-2 is a useful test to detect acute pancreatitis and to evaluate disease severity. Trypsinogen-2 serum levels are also implicated in pancreatic cancer.

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