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Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that is induced by intraplaque hemorrhage and degrades free heme and releases ferrous iron, which is rapidly sequestered by ferritin. In vitro studies have shown that binding of hemoglobin to hemoglobin scavenger receptor (CD163) induces HO-1 and the anti-inflammatory mediator interleukin (IL)-10. We immunohistochemically examined the relationship between CD163 expression in macrophages and intraplaque hemorrhage, HO-1, IL-10, and ferritin using coronary atherectomy specimens from patients with stable (SAP) or unstable angina pectoris (UAP). A total of 67 patients underwent atherectomy for SAP (n = 33) or UAP (n = 34). Samples were stained with antibodies against smooth muscle cells, macrophages, glycophorin- A (a protein specific to erythrocyte membranes), CD163, HO-1, IL-10, and ferritin. To identify cell types of HO-1-positive cells, double immunostaining was also performed. Double immunostaining for HO-1 and macrophages revealed that the vast majority of HO-1-positive cells were macrophages. Morphometric analysis demonstrated that CD163-positive macrophage score and the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas were significantly higher in UAP than in SAP patients (CD163, P < .005; glycophorin-A, P < .0001; HO-1, P < .0001; IL-10, P < .005; ferritin, P = .0001). Moreover, CD163-positive macrophage score was positively associated with the percentage of glycophorin-A-, HO-1-, IL-10-, and ferritin-positive areas (glycophorin-A, r = 0.60, P < .0001; HO-1, r = 0.67, P < .0001; IL-10, r = 0.45, P < .0005; ferritin, r = 0.61, P < .0001). These findings suggest that enhanced expression of HO-1 and HO-1-related atheroprotective molecules plays an important role in exerting anti-inflammatory, antioxidant, and scavenging functions, which could contribute to plaque stabilization. [ABSTRACT FROM AUTHOR]

Abstract: Macrophages are key players of the immune system and express a variety of surface receptors. CD163 is one such receptor which belongs to the scavenger receptor cysteine-rich super family (SRCR-SF) class B. It has four isoforms which differ in the structure of their cytoplasmic domains and putative phosphorylation sites. Expression of CD163 is tightly regulated with a general tendency of anti-inflammatory signals to induce its synthesis, while pro-inflammatory signals downregulate its expression. Previously the molecule has been shown to act as a receptor for hemoglobin–haptoglobin complexes. However, it also plays a crucial role in the control of inflammatory processes by induction of anti-inflammatory pathways. Soluble CD163, which is generated via ectodomain shedding, serves as a potential diagnostic tool in a variety of disease states, such as inflammation, atherosclerosis, transplant rejection and carcinoma. Recently, CD163 has been identified as a promising target for cell directed therapy. In this review we aim to summarize the current knowledge of CD163. [Copyright &y& Elsevier]

Abstract: Background: The soluble form of the haptoglobin–hemoglobin (Hp–Hb) scavenger receptor (sCD163) is a specific plasma/serum marker for macrophage activity. Here, we have characterized molecular forms in serum and investigated a role of sCD163 as a binder of Hp–Hb complexes. Methods: The sCD163 species in serum (from 50 healthy subjects and 29 patients) were measured with domain-specific ELISAs, purified from serum (from 6 individuals) by affinity chromatography and identified by western blotting and MALDI-TOF/TOF mass spectrometry. Binding to Hp–Hb complexes was investigated by gel-chromatography, surface plasmon resonance (SPR) analyses, and inhibition of Hp–Hb endocytosis in CD163-transfected Chinese hamster ovary (CHO) cells. Results: By using C- and N-terminal-specific ELISAs, no sCD163 concentration differences in plasma were seen, thus indicating a homogenous sCD163 species. Affinity-purified sCD163 from serum migrated as a single band of 130kDa, and spanned at least 945 amino acids (94%) of the total extra-cellular part of CD163. In solution sCD163 only weakly competed for Hp–Hb uptake in CD163-expressing cells, and Hp–Hb saturation of sCD163 in serum was only seen with large excess of Hp–Hb complexes. However, upon immobilisation, recombinant sCD163 bound Hp–Hb with high affinity. This suggests that Hp–Hb is less dissociable when bound to the membrane form of CD163, presumably because of the di- or multivalent nature of Hp–Hp complexes in terms of CD163 binding. Conclusions: Serum sCD163 is a homogenous protein covering more than 94% of the CD163 ectodomain including the Hp–Hb-binding region. However, CD163 is a poor competitor of Hp–Hb uptake, probably because of its soluble nature, where Hp–Hb cannot take advantage of receptor cross-linkage. [Copyright &y& Elsevier]

We previously proposed that erythrophagocytosis and iron metabolism by macrophages may contribute to iron-driven oxidative stress in atherogenesis. Recent studies have indicated that the macrophage hemoglobin scavenger receptor (HbSR/CD163) is a key molecule in the process of removing hemoglobin released from senescent erythrocytes. In this study we investigated erythrophagocytosis and its relation to ferritin accumulation and the involvement of CD163 in ferritin induction in human atheroma lesions. Normal and atherosclerotic human arterial segments obtained at autopsy and surgery were collected for iron histochemistry, hemoglobin and ferritin immunohistochemistry, and computerized image analysis. The lesion-dependent accumulation of ferritin and hemoglobin was seen in atherosclerotic carotid and coronary arteries. The immunoreactivity of hemoglobin was significantly correlated to the same regions of ferritin immunoreactivity on serial sections. The staining intensity of hemoglobin and ferritin was also significantly correlated. Hemoglobin deposition is often associated with microvessels adjacent to the lipid core areas in advanced lesions, where most CD68-positive macrophages were. CD163 expression appeared in both early and advanced lesions. The accumulation of tissue iron and ferritin also frequently occurs in CD163-positive and vesselrich regions in the advanced atheroma. Although they were not always correspondingly positive on the serial sections, tissue iron and ferritin were significantly correlated. We conclude that erythrophagocytosis and hemoglobin catabolism by macrophages contribute to iron deposition and ferritin induction in human atheroma. The involvement of CD163 during ferritin induction may play an important role in modulating inflammatory processes in atherogenesis. [ABSTRACT FROM AUTHOR]