Clinical significance of sCD163 and its possible role in asthma (Review)

Abstract

Macrophages exert important functions in the balance and efficiency of immune responses, and participate in innate and adaptive immunity. The proinflammatory actions of macrophages are implicated in autoimmune diseases. Unlike classically activated M1 macrophages, the alternatively activated cluster of differentiation (CD)163+ and CD206+ M2 macrophages are involved in tissue repair and wound healing, and use oxidative metabolism to support their long‑term functions. CD163 is a member of the scavenger receptor superfamily, categorized into class B, and its soluble(s) form, sCD163, is a marker of activated M2 macrophages. CD163 is selectively expressed in cells of the monocyte and macrophage lineages; however, its biological role has yet to be elucidated. The expression of sCD163 is markedly induced by anti‑inflammatory mediators, such as glucocorticoids and interleukin‑10, whereas it is inhibited by proinflammatory mediators, such as interferon‑γ. These findings suggest that CD163 may serve as a potential target for the therapeutic modulation of inflammatory responses. The concentration of sCD163 in blood is associated with acute and chronic inflammatory processes in autoimmune disorders of connective tissue, fat metabolism and cardiovascular diseases, and it can be used for the assessment of cancer prognosis. A role for sCD163 in the pathogenesis of asthma has also been proposed. The present review serves to present the available knowledge concerning the implication of sCD163 in the pathophysiological mechanisms of asthma, and evaluate its potential as a biomarker and possible therapeutic target for asthma.

Figure 1.

Macrophages serve a key role in regulating the activation and resolution of immune responses. The induction of M0 macrophages by inflammatory mediators, such as IL-4 and IL-10, results in the differentiation of M2 macrophages. IL-17 (in a Th17 environment) prevents macrophage apoptosis, whereas IFN-γ (during Th1 inflammation) promotes apoptosis of macrophages. NE stimulates CD163 shedding, a marker of M2 macrophage activation. Macrophages effectively eliminate apoptotic neutrophils via phagocytosis. IL, interleukin; Th, T helper; IFN, interferon; NE, neutrophil elastase; CD, cluster of differentiation; Treg, T regulatory.

Figure 2.

Shedding of sCD163. Several inflammatory signals have been demonstrated to induce ectodomain shedding of sCD163 in vitro. ADAM17/10 mediates shedding of CD163 and TNF-α upon stimulation by inflammatory stimuli. CD163 and pro-TNF-α are rapidly cleaved from the surface of activated macrophages by an ADAM17/10-mediated mechanism. The half-life of sCD163 is much longer than that of TNF-α. Similar palindromic sequences in human CD163 (1044Arg-Ser-Ser-Arg) and pro-TNF-α (78Arg-Ser-Ser-Ser-Arg) were identified by a comparison of the sequences of the juxtamembrane region of the proteins. s, soluble; CD, cluster of differentiation; ADAM, a disintegrin and metalloproteinase; TNF, tumor necrosis factor; IL, interleukin; Hb, hemoglobin; M-CSF, macrophage-colony stimulating factor; IFN, interferon; LPS, lipopolysaccharide; CXCL, (C-X-C motif) ligand.

Figure 3.

A hypothetical model of Hp-independent intravascular detoxification and clearance of cell-free Hb by CD163. Hb induces shedding of CD163 into the plasma and the produced sCD163 captures and quenches the residual redox-reactive Hb. Subsequently, IgG interacts with the sCD163-Hb complex. The sCD163-Hb-IgG complex then elicits an autocrine loop of endocytosis via FcγR on monocytes and subsequent recycling of the internalized sCD163 via endosomes to restore CD163 homeostasis in the membrane, whereas the internalized Hb is catabolized by HO-1. Hp, haptoglobin; Hb, hemoglobin; CD, cluster of differentiation; s, soluble; Ig, immunoglobulin; FcγR, Fcγ receptor; HO, heme oxygenase; TLR, Toll-like receptor.