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Originally published online as doi:10.1189/jlb.0706453 on April 25, 2007

Published online before print April 25, 2007
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(Journal of Leukocyte Biology. 2007;82:106-110.)
© 2007 by Society for Leukocyte Biology

CD163-expressing monocytes constitute an endotoxin-sensitive Hb clearance compartment within the vascular system

Christian A. Schaer1, Florence Vallelian1, Alexander Imhof, Gabriele Schoedon and Dominik J. Schaer2

Department of Medicine, University Hospital, Zurich, Switzerland

2 Correspondence: Medical Clinic Research Unit, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: dominik.schaer{at}usz.ch

ABSTRACT

Hemoglobin (Hb) is released into the circulation during intravascular hemolysis and exerts toxic effects through oxidative damage and NO scavenging. According to the traditional concept of Hb clearance, free Hb is bound to the plasma protein haptoglobin (Hp), and the Hb-Hp complexes are cleared by liver and spleen macrophages via the Hb scavenger receptor CD163. Using a novel whole blood assay, we demonstrate that clearance of Hb-Hp is also mediated by CD14high/CD64high peripheral blood monocytes, which express CD163. Hb-Hp uptake by these cells is Ca2+-dependent and is abrogated by the addition of CD163-blocking antibodies. Accordingly, LPS treatment reduces monocyte surface CD163 and impairs Hb-Hp uptake. Monocytes likely mediate Hp-Hb uptake in vivo, as a high expression of the heme breakdown enzyme heme oxygenase-1 was observed in CD163+ monocytes but not in other leukocyte populations obtained from healthy blood donors. We propose that CD163-mediated Hb-Hp uptake by peripheral blood monocytes constitutes an Hb-Hp clearance pathway, which acts at the site of intravascular hemolysis to reduce Hb-Hp circulation time and toxicity. Disruption of monocyte Hb-Hp clearance may increase Hb-Hp toxicity and contribute to the pathogenesis of systemic inflammatory diseases associated with reduced monocyte CD163 expression.

Key Words: macrophage • hemolysis • hemoglobin • haptoglobin

The majority of hemoglobin (Hb) iron present in aged RBCs is recycled for use in erythropoiesis after these cells are phagocytosed by macrophages of the liver and spleen [1 ]. However, even under physiologic conditions, ~10% of Hb is released into plasma after intravascular hemolysis, and considerably higher amounts of cell-free Hb can be observed during infection or in acquired or inherited hemolytic diseases such as paroxysmal nocturnal hemoglobinuria or sickle cell anemia [2 ].

Cell-free Hb exerts its toxic effects through distinct mechanisms. Heme is a potent oxidant, and oxidative damage of endothelial cells (ECs) and plasma proteins such as lipoproteins has been implicated in the pathogenesis of atherosclerosis [3 4 5 ]. In recent years, the disappointing experience with Hb-based blood substitutes and the extensive investigation of the mechanisms involved in the vasculopathy of patients with chronic hemolysis have revealed that Hb scavenging of NO is another major determinant of cell-free Hb toxicity [6 7 8 9 ]. The reduced bioavailability of NO is thought to blunt endothelium-mediated vaso-relaxation and subsequently cause hypertension, particularly within the pulmonary circulation. Thus, pulmonary hypertension and subsequent right ventricular failure are leading causes of disability and death in patients with sickle cell disease [10 ].

Upon intravascular hemolysis, cell-free Hb is bound tightly to the plasma protein haptoglobin (Hp). Circulating Hb-Hp complexes are thought to be cleared by spleen and liver macrophages, which express high levels of the Hb-Hp scavenger receptor CD163 [11 12 13 ]. After depletion of plasma Hp during intensive intravascular hemolysis, non-Hp-bound Hb is also endocytosed by macrophages through a low-affinity, CD163-Hb-binding site [14 ]. However, according to the current model of cell-free Hb clearance, the passage of cell-free Hb from the site of erythrocyte destruction to the liver/splenic circulation would require a considerable amount of time. As NO scavenging and heme oxidative reactions are fast and irreversible, an intravascular Hb clearance pathway acting at the site of erythrocyte destruction could reduce the circulation time of free Hb significantly and thus limit the physiological side-effects of cell-free Hb. However, to our knowledge the Hb clearance capacity of circulating blood cells has not been examined yet.

Using a novel, whole blood assay for cellular Hb-Hp uptake, we examined whether peripheral blood leukocytes could serve as an intravascular Hb clearance compartment. The examination of whole blood excluded the functional artifacts, which arise from cell purification procedures.

Freshly drawn, heparinized blood (100 µL) from healthy volunteers, who gave written, informed consent, were diluted with Gey’s balanced salt solution (1:1, Sigma Chemical Co., St. Louis, MO, USA). The whole blood mixture was then incubated with 3 µg/ml Alexa 633-labeled Hp (Hp633), which had been mixed previously with an equimolar amount of Hb to allow for the formation of stable, fluorescent Hb-Hp633 complexes, as described [14 ]. As significant amounts of endotoxin have been detected in commercial preparations of Hb, we used highly purified Hb (Hemosol, Ontario, Canada) to avoid leukocyte activation during the assay, which could eventually affect the experiments through induction of CD163 shedding. The Hb used in our studies was tested by gene array analysis, not to induce inflammatory macrophage activation. The Hb-Hp blood mixture was incubated in a 37°C water bath for 30 min, and erythrocytes were lysed subsequently by addition of EC-lysis solution (ammonium chloride, 8.3 mg/ml; potassium hydrogen carbonate, 1 mg/ml; EDTA, 0.037mg/ml). EDTA was included in the lysis solution to prevent further Hb-Hp uptake by leukocytes and to remove bound, noningested ligand [14 ]. Erythrocyte lysis was allowed to proceed for 15 min, after which time, leukocytes were washed twice in PBS and subsequently stained with mAb against CD14 (FITC) and CD64 (PE; Becton Dickinson, San Jose, CA, USA) as described elsewhere [15 ]. Cells were analyzed with a FACSCalibur (Becton Dickinson) equipped with a 488-nm argon laser and a 633-nm helium-neon laser. Data were analyzed using CellQuest (Becton Dickinson) and visualized with WinMDI (Version 2.6) software. For analysis of cell surface expression of CD163, leukocytes were stained with an allophycocyanin (APC)-labeled anti-CD163 antibody (R&D Systems, Minneapolis, MN, USA).

For RT-PCR analysis of in vivo heme oxygenase-1 (HO-1) expression by leukocytes, leukocyte subpopulations were isolated by Ficoll-Paque centrifugation and subsequent plastic adherence for 1 h as described previously [13 ]. Adherent monocytes and nonadherent lymphocytes had a purity of >90%, as determined by FACS analysis. Granulocytes were obtained by hypotonic red cell lysis of the granulocyte/erythrocyte fraction after Ficoll-Paque separation of blood. RNA isolation and RT-PCR were performed as described [14 ]. The following primer pairs were used for the amplification of HO-1, CD163, and GAPDH (control gene): HO-1 forward: 5'-AGGGTGATAGAAGAGGCCAAGACT-3'; HO-1 reverse: 5'-TTCCACCGGACAAAGTTCATGGC-3', GAPDH forward: 5'-AACAGCGACACCCACTCCTC-3'; GAPDH reverse: 5'-GGAGGGGAGATTCAGTGTGGT-3'; CD163 forward: 5'-ACATAGATCATGCATCTGTCATTTG-3'; CD163 reverse: 5'-CATTCTCCTTGGAATCTCACTTCTA-3'. Immunofluorescence staining of PBMC for HO-1 was performed on paraformaldehyde-fixed cytocentrifugation slides using an anti-human-HO-1 mAb (StressGen, Victoria, BC, Canada) and an Alexa 594 goat anti-mouse antibody (Molecular Probes, Eugene, OR, USA). Samples were examined with a motorized Carl Zeiss epifluorescence Axioskope 2 equipped with an AxioCam MR digital camera and AxioVision 4.1 software (Zeiss, Thornwood, NY, USA). Z-stacks were acquired with twofold oversampling in the axial z-axis and were deconvoluted using a constrained iterative algorithm. Visualization was performed with AxioVision Inside4D software (Zeiss). Images representing single sections through three-dimensional volume stacks are shown.

As illustrated in Figure 1A , Hb-Hp633 uptake is a functional property of a distinct leukocyte subpopulation, which could be identified unequivocally as monocytes, based on their light-scatter pattern and high-level expression of CD14 and CD64. We did not observe uptake of even minute amounts of Hb-Hp633 by granulocytes or lymphocytes.


Figure 1
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  		Figure 1. CD163-positive monocytes constitute a distinct Hb-Hp clearance compartment in peripheral blood. (A) Heparinized blood was incubated with (upper right panel) or without (upper left panel) Hb-Hp633, and red cells were lysed. The remaining white blood cells were stained with CD14 (FITC) and CD64 (PE). FACS analysis revealed that only one distinct cell population displayed significant Alexa 633 fluorescence above background, which represents Hb-Hp633 uptake (positive cell population colored in red). This cell population was identified as the monocyte cell lineage based on its specific light-scatter pattern (middle panels). This was confirmed by the high CD14/CD64 expression detected on the Hb-Hp633-positive cells (lower panels). FSC, Forward-scatter. (B) CD14high/CD64high monocytes express CD163, as demonstrated, using an APC-conjugated anti-CD163 antibody. The CD163high/CD14high/CD64high monocyte population is colored in blue.

 
To estimate the potential quantitative relevance of Hb-Hp endocytosis by peripheral blood monocytes, we have compared the Hb-Hp uptake observed in our whole blood assay with the Hb-Hp uptake capacity of PBMC-derived macrophages from the same donors cultured in vitro for 8 days (Fig. 2 ). Although Hb-Hp uptake is much more heterogeneous in cultured macrophages than in monocytes, the mean fluorescence of the heterogenous cell population after Hb-Hp incubation is similar to that of monocytes. Therefore, the monocyte capacity to ingest circulating Hb-Hp complexes seems to be comparable with the capacity of differentiated macrophages, thus supporting a physiologic role of circulating monocytes as a Hb clearance compartment.


Figure 2
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  		Figure 2. Comparison of Hb-Hp endocytosis capacity of macrophages and peripheral blood monocytes. (A) Human PBMC-derived monocytes (mono) were cultured for 8 days to allow macrophage (macro) differentiation (as described in ref. [16 ]). The cells were then incubated with fluorescent (fl) Hb-Hp633 for 30 min, washed, and subsequently analyzed by FACS. In parallel, peripheral blood monocyte Hb-Hp633 uptake was determined in whole blood drawn from the same donor. Shown are mean fluorescence values ± SD from three independent experiments. (B) Representative fluorescence histograms of peripheral blood monocytes and macrophages after Hb-Hp633 endocytosis. The second example of monocyte Hb-Hp uptake is derived from a patient under glucocorticoid treatment (mono GC). The higher mean fluorescence and thus higher Hb-Hp633 uptake are compatible with the known glucocorticoid induction of CD163 expression and subsequent enhancement of macrophage Hb-Hp uptake in vitro.

 
Expression of the Hb scavenger receptor CD163 is highly induced during the differentiation of peripheral blood monocytes into mature macrophages. However, whether circulating monocytes express significant levels of CD163 is a topic of debate [17 18 19 20 ]. Therefore, we have re-examined whether monocytes express this candidate Hb clearance receptor. As monocyte autofluorescence is virtually absent in the far red APC excitation/emission range, we have used a novel, APC-conjugated mAb to CD163 to significantly enhance the signal-to-noise ratio of our FACS analysis. Our results provide definitive proof that all CD14high/CD64high monocytes also express CD163 (Fig. 1B) . The fact that the Ca2+-dependent Hb-Hp uptake by monocytes was abolished by the addition of excess {alpha}–{alpha} diaspirin cross-linked tetrameric Hb ({alpha}–{alpha} DBBF-Hb), which is an Hp-independent CD163 ligand, suggests that a receptor-dependent mechanism is involved in monocyte Hb-Hp uptake [14 ]. Further, CD163 seems to play a crucial and possibly nonredundant role in the clearance of free Hb in the circulating blood, as monocyte Hb-Hp uptake was inhibited completely by a polyclonal antibody previously shown to block the Hb-Hp interaction with CD163 (Fig. 3A ) [12 , 14 ]. As an indirect measure of active Hb clearance and catabolism by monocytes in vivo, we examined peripheral blood leukocyte expression of the essential heme breakdown enzyme HO-1, which is induced by CD163-mediated Hb uptake. As illustrated in Figure 3B , CD163-positive monocytes but not CD163-negative lymphocytes express detectable levels of HO-1 antigen. Consistent with this finding, HO-1 mRNA was detected in freshly isolated monocytes, which also contained high CD163 mRNA levels, but not in lymphocytes or granulocytes (Fig. 3C) .


Figure 3
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  		Figure 3. Monocyte clearance of Hb-Hp is mediated by CD163 and is blocked by LPS-induced monocyte activation. (A) Heparinized whole blood was incubated with Hb-Hp633 in the presence or absence of {alpha}–{alpha} DBBF-Hb (1000 µg/ml), polyclonal anti-CD163 IgG (aCD163; 10 µg/ml), or EDTA. Monocyte Hb-Hp633 uptake is inhibited completely by EDTA, confirming the Ca2+ dependence of this process. It is important that it is also inhibited by {alpha}–{alpha} DBBF-Hb and anti-CD163, demonstrating that CD163 is required for monocyte Hb clearance. (B) Freshly prepared mononuclear cells were stained for CD163 (green, Alexa 488) and HO-1 (red, Alexa 594). CD163/HO-1-positive cells, but not CD163/HO-1-negative lymphocytes, display active Hb-Hp uptake capacity, as indicated by the presence of intracellular fluorescent Hb-Hp after 15 min of incubation with fluorescent Hb-Hp647 (20 µg/ml), which was performed immediately prior to the fixation/staining procedure. Nuclei were counterstained with 4', 6, diamidino-2-phenylindole (blue). (C) Isolated monocytes (Mo), granulocytes (Gr), and lymphocytes (Ly) were examined for HO-1 mRNA expression by RT-PCR (30 amplification cycles). High levels of HO-1 expression were detected exclusively within the CD163-positive monocyte population. GAPDH was amplified from all samples to verify cDNA integrity. (D) Human peripheral blood monocytes were isolated by adherence of PBMCs on glass coverslips for 120 min. Subsequently, the cells were incubated with or without 20 µM monensin for 60 min, fixed, permeabilzed, and stained for CD163 using a polyclonal anti-CD163 antibody and Alexa 594 goat anti-rabbit antibody. Compatible with the known activity of monensin to inhibit receptor-recycling after endocytosis, the intracellular CD163 accumulates in coarse vesicles. Although CD163 disappears from the cell surface upon monensin treatment, there is no change in total cellular CD163 (MW 130 kD), as determined by Western blot. (E) Heparinized whole blood was incubated with LPS (1 µg/ml) or the receptor recycling inhibitor monensin (mon; 20 µM) for 60 or 120 min. Hb-Hp633 uptake and cell surface expression of CD163, CD14, and CD64 were then determined by FACS. Data are expressed as percent of untreated samples and represent mean ± SD from three independent experiments.

 
Upon macrophage activation, the CD163 ectodomain is shed by a metalloproteinase-dependent mechanism [21 22 23 ]. Accordingly, increased levels of soluble CD163 have been observed after experimental endotoxin administration [21 ], during macrophage activation syndromes (hemophagocytic syndromes) [23 ], and during sepsis [23 ]. Recently, engagement of the cell surface TLR2, TLR4, and TLR5 by their respective ligands was shown to play a pivotal role in CD163 shedding under inflammatory conditions [24 ]. However, the functional consequences of CD163 shedding have not been examined yet. Thus, we analyzed whether leukocyte stimulation by LPS, a bacterial endotoxin that acts as a potent monocyte stimulator through ligation of TLR4, impairs the ability of monocytes to endocytose Hb-Hp. After incubation of whole blood with endotoxin for 60 or 120 min, monocyte expression of cell surface CD163 was reduced to 26.6 ± 8.3% and 15.8 ± 5.0% (mean± SD) of the baseline levels, respectively. Also, endocytosis of fluorescent Hb-Hp was reduced significantly to 46.2 ± 12.4% and 30.9 ± 8.9% (mean±SD), respectively (Fig. 3E) . In contrast to the profound loss of cell surface CD163, LPS induced an increase in cell surface CD14 and CD64 expression, which reflects the inflammatory activation of monocytes. Unlike LPS, free Hb had no effect on CD163 cell surface expression (data not shown). The latter observation implies that CD163 is not degraded after internalization but instead, recycles back to the cell surface, as is does in macrophages and in CD163-transfected human embryo kidney 293 cells [16 ]. In fact, receptor recycling may account for the ability of circulating monocytes to mediate clearance of intravascular Hb, despite quantitatively low expression of CD163. To substantiate this hypothesis further, we treated monocytes with monensin, a potent inhibitor of receptor recycling from early endosomes to the cell surface [25 ]. Although monensin treatment for 60 min did not affect total cellular CD163 content of monocytes, as indicated by Western blot analysis (Fig. 3D) , cell surface CD163 expression and Hb-Hp endocytosis were reduced to 25.1% and 5.1%, respectively (Fig. 3E) . Compatible with its activity as an inhibitor of receptor recycling, monensin induced accumulation of CD163 in coarse intracellular vesicles (Fig. 3D) . Monensin treatment did not reduce cell surface expression of CD64 and CD14, thus making an unspecific effect unlikely.

In this study, we have demonstrated that clearance of free Hb by the scavenger receptor CD163 is a novel, physiologic function of peripheral blood monocytes. In contrast to the traditional concept, which proposes that Hb clearance occurs within the liver and spleen, we propose that "intravascular Hb clearance" limits the circulation time of free Hb and thus, prevents systemic toxicity of physiologic, intravascular hemolysis. The fact that CD163-mediated Hb clearance is strikingly reduced by the inflammatory activation of monocytes may indicate that impaired clearance of free Hb contributes to the pathogenesis of systemic inflammatory diseases by increasing oxidative damage and vascular NO scavenging. The quantitative assessment of CD163-mediated Hb endocytosis by peripheral blood monocytes using the assay described here will allow for further clinical investigations aimed at understanding the disturbances in monocyte Hb clearance associated with human diseases.

ACKNOWLEDGEMENTS

This work was supported by the Foundation for Research at the Medical Faculty, University of Zurich, the Hartmann-Muller Foundation, and the HOLCIM Foundation (all to D. J. S.).

FOOTNOTES

1 These authors contributed equally to this work. Back

Received July 17, 2006; revised December 11, 2006; accepted January 16, 2007.

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