Calprotectin in rheumatic diseases

Abstract

Calprotectin is a heterodimer formed by two proteins, S100A8 and S100A9, which are mainly produced by activated monocytes and neutrophils in the circulation and in inflamed tissues. The implication of calprotectin in the inflammatory process has already been demonstrated, but its role in the pathogenesis, diagnosis, and monitoring of rheumatic diseases has gained great attention in recent years. Calprotectin, being stable at room temperature, is a candidate biomarker for the follow-up of disease activity in many autoimmune disorders, where it can predict response to treatment or disease relapse. There is evidence that a number of immunomodulators, including TNF-α inhibitors, may reduce calprotectin expression. S100A8 and S100A9 have a potential role as a target of treatment in murine models of autoimmune disorders, since the direct or indirect blockade of these proteins results in amelioration of the disease process. In this review, we will go over the biologic functions of calprotectin which might be involved in the etiology of rheumatic disorders. We will also report evidence of its potential use as a disease biomarker. Impact statement Calprotectin is an acute-phase protein produced by monocytes and neutrophils in the circulation and inflamed tissues. Calprotectin seems to be more sensitive than CRP, being able to detect minimal residual inflammation and is a candidate biomarker in inflammatory diseases. High serum levels are associated with some severe manifestations of rheumatic diseases, such as glomerulonephritis and lung fibrosis. Calprotectin levels in other fluids, such as saliva and synovial fluid, might be helpful in the diagnosis of rheumatic diseases. Of interest is also the potential role of calprotectin as a target of treatment.

Keywords: Calprotectin; S100A8/A9; biomarker; inflammation; rheumatic diseases; rheumatoid arthritis.

Figure 1

Effects of calprotectin on the cells implicated in the pathogenesis of rheumatic diseases. CLP is mainly produced by activated monocytes and granulocytes and mediates the production of pro-inflammatory cytokines and chemokines, cell activation, and apoptosis in targeted cells. CLP induces the expression of further CLP with a consequent positive autocrine and paracrine feedback loop. (A color version of this figure is available in the online journal.)

Figure 2

Intracellular functions of calprotectin in polimorphonucleates and monocytes. CLP is a heterodimer composed of two proteins, S100A8 and S100A9. A danger signal molecule, such as LPS and CLP itself, can bind TLR4 and RAGE directly or through carboxylated glycans triggering inflammation via-NF-ĸB which translocates into the nucleus (a). In the nucleus NF-ĸB induces the expression of further S100A8 and S100A9. CLP is secreted through an energy dependent process, which requires PKC activation (b) and/or the interaction with microtubules (e). TLR4 or RAGE binding by CLP can induce the expression of proinflammatory cytokines and adhesion molecules, such as CD11b and CD18, contributing to the amplification of the inflammatory response and leading to leukocyte adhesion to the endothelium (c). In the presence of calcium, S100A9 subunit binds arachidonic acid and transports it to the NADPH oxidase complex expressed in the plasma membrane with a PKC-dependent mechanism. S100A9 transfers arachidonic acid to gp91^phox subunit of the NADPH complex while S100A8 binds to p67^phox and rac-2 subunits. Activated NADPH oxidase produces reactive oxygen species which are crucial for the inflammatory activity of granulocytes (d). In the presence of calcium, S100A8 and S100A9 also form heterotetrameters which translocate to the cell membrane and allow tubulin polymerization, microtubules bundling and stabilization of tubulin filaments. CLP regulates the cytoskeleton cell migration (e). (A color version of this figure is available in the online journal.)