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(Journal of Leukocyte Biology. 2001;69:248-252.)
© 2001 by Society for Leukocyte Biology

Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1 during differentiation of human monocytes to macrophages

Andreas Kaufmann^*, Robert Salentin^*, Diethard Gemsa^* and Hans Sprenger

^* Institute of Immunology, Philipps University, Marburg; and
Institute of Laboratory Medicine, Leopoldina-Hospital, Schweinfurt, Germany

Correspondence: Andreas Kaufmann, Ph.D., Institute of Immunology, Philipps University Marburg, Robert-Koch-Str. 17, D-35037 Marburg, Germany. E-mail: kaufmana{at}mailer.uni-marburg.de

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Chemokines and their receptors regulate migration of leukocytes under normal and inflammatory conditions. In this study, we analyzed the CC chemokine receptor (CCR) expression of monocytes differentiating in vitro to macrophages. We observed a time-dependent change of expression and functional responsiveness of CCR1, CCR2, and CCR5 within 48 h. Whereas freshly harvested monocytes were strongly attracted by monocyte chemotactic protein 1 (MCP-1), a specific ligand for CCR2, only a weak response was observed to macrophage inflammatory protein 1 (MIP-1), which binds to CCR1 and CCR5. In striking contrast, differentiated macrophages displayed a strong chemotactic response to MIP-1 and only a weak response to MCP-1. These findings were paralleled by intracellular calcium shifts. During the time course of monocyte to macrophage differentiation, mRNA levels and surface expression of CCR2 decreased, whereas that of CCR1 and CCR5 increased. The time-dependent switch from CCR2 on monocytes to CCR1 and CCR5 on mature macrophages reflects a functional change belonging to the differentiation process of monocytes to macrophages and may form the basis for a differential responsiveness of monocytes and macrophages to distinct sets of chemokines.

Key Words: chemokine • chemokine receptors

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Monocytes/macrophages are multifunctional cells that play an important role in host defense [¹ ]. Bone marrow-derived monocytes migrate from the blood into surrounding tissue, a process called diapedesis, and differentiate into macrophages. The differentiation of monocytes to macrophages is accompanied by changes in their functional response and depends on various signals [^{2 3 4 5} ]. Under in vitro conditions, human blood monocytes display similar changes and turn phenotypically and functionally into tissue macrophages [⁶ , ⁷ ].

Members of the superfamily of chemokines are potent low-molecular-weight chemoattractant cytokines, which are the main factors recruiting effector cells during inflammatory diseases [⁸ , ⁹ ]. According to the position of the first two cysteine residues the chemokines can be subdivided into different groups that attract and activate distinct leukocyte populations. The subfamily of CC chemokines, such as monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1) preferentially act on mononuclear cells. The role of MCP-1 and MIP-1 as major chemoattractants in host defense and inflammation has been reported by previous in vivo studies [¹⁰ , ¹¹ ]. MCP-1- or MIP-1-deficient animals show an impaired recruitment of monocytes in several inflammatory situations, as well as a substantial reduction of infiltrating mononuclear cells after viral infections. All chemokine receptors identified so far are members of the seven-transmembrane-domain rhodopsin-like superfamily of receptors and are coupled to GTP-binding proteins. Monocytes/macrophages have recently been shown to express the CC chemokine receptors CCR1, CCR2, and CCR5 [¹² ]. Most chemokine receptors are not specific for only one ligand, but promiscuously bind to more than one chemokine. Although MCP-1 is a specific ligand for CCR2, MIP-1 mediates its signal via CCR1 and CCR5.

We report that differentiation of monocytes to macrophages was accompanied by a switch from CCR2 to CCR1/CCR5, which coincided with an altered responsiveness to different chemokines.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Cell preparation and culture
Human monocytes were isolated from buffy coats of healthy donors. After separation of the mononuclear cells through the use of Ficoll-Hypaque density centrifugation, the monocytes were enriched by elutriation as previously described [¹³ ] and subsequently cultured in Teflon tubes (Savillex, Minnetonka, MN). These culture conditions did not influence the differentiation process of monocytes as determined by an increased phagocytosis. Furthermore, monocytes cultured in Teflon tubes showed similar alterations in their inducible chemokine and cytokine profile when compared with monocytes cultured in plastic dishes. However, monocytes from Teflon cultures were easier to recover, and cell damage or nonspecific activation by scraping strongly adherent cells from plastic surfaces was avoided. At various times of differentiation, the cultures were placed on ice for 30 min, extensively resuspended, washed twice in phosphate-buffered saline (PBS), and immediately used for further experiments.

Chemotaxis assay and calcium flux
Chemotaxis assays were performed in 48-well microchemotaxis chambers with 1 x 10⁵ cells in the upper chamber as previously described in detail [¹⁴ ]. Intracellular calcium concentration [Ca²⁺]_i changes in Fura-2-loaded cells were monitored after chemokine stimulation by excitation wavelengths at 340 and 380 nm and an emission wavelength at 510 nm on a fluorescence spectrometer (BMG Lab Technologies, Offenburg, Germany) as described elsewhere [¹⁵ ] according to the technique reported by Grynkiewicz et al. [¹⁶ ].

Measurement of chemokine receptor surface expression
Cells (2 x 10⁶/mL) were incubated with biotinylated anti-human CCR1, CCR2, CCR5 (R & D Systems, Wiesbaden, Germany), or isotype-specific goat anti-mouse (PharMingen, Hamburg, Germany) monoclonal antibody, washed twice, and subsequently incubated with streptavidin-PE (PharMingen). To amplify the received fluorescence signal, cells were further incubated with biotinylated anti-avidin D antibody (Vector Laboratories, Burlingame, CA), followed by a second incubation with streptavidin-PE conjugate. The samples were analyzed on a FACScan flow cytometer (Becton Dickinson, Heidelberg, Germany).

RNase protection assay
Total RNA from 5 x 10⁶ cells was extracted with the use of Trizol^® reagent (Life Technologies, Karlsruhe, Germany). A multi-probe template set hCR5, containing DNA templates for CCR1, CCR3, CCR4, CCR5, CCR8, CCR2a+b, CCR2a, CCR2b, L32, and GAPDH, was purchased from PharMingen. Ten micrograms of RNA was hybridized overnight to the probe set containing [³²P]UTP-labeled transcripts with the use of a Direct Protect^® kit (Ambion, Austin, TX) according to the manufacturer’s protocol. After digestion of single-stranded RNA with RNase A/T1 (Ambion), the samples were analyzed on denaturing urea/polyacrylamide gels. Bands were detected by autoradiography.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Differentiation-dependent responsiveness of monocytes to MCP-1 and MIP-1
In vitro differentiating macrophages derived from human peripheral blood monocytes were tested for their chemotactic responsiveness. As shown in Figure 1A , fresh monocytes were strongly attracted by MCP-1. The more the monocytes differentiated to macrophages, the more they lost the capacity to migrate in response to MCP-1. In striking contrast, fresh human monocytes were only weakly attracted by MIP-1 (Fig. 1A , left panel). However, when compared with MCP-1, the opposite pattern was found for MIP-1: the more the cells differentiated to macrophages, the stronger was their response to MIP-1.

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Figure 1. Functional response of differentiating monocytes to MCP-1 and MIP-1. (A) The chemotactic response of in vitro cultured monocyte was assayed by a 48-well microchemotaxis chamber technique. At different stages of differentiation, cell migration in response to MIP-1 and MCP-1 (50 ng/mL) was determined. The results are expressed as the difference of total number of chemokine-induced cell migration and migration to control medium (specific chemotaxis ± SD). One representative analysis out of eight is shown. (B) Differentiating monocytes were loaded with Fura-2/AM and sequentially stimulated with MIP-1 or MCP-1 (50 ng/mL) indicated by the arrow. The [Ca2+]i-dependent fluorescence changes were recorded. Representative data out of six independent experiments is shown.

MCP-1 and MIP-1-induced calcium shifts in differentiating monocytes
The differentiation-dependently altered chemotaxis of monocytes was further supported by the results obtained from intracellular calcium shifts. As shown in Figure 1B (right panel), undifferentiated monocytes were highly responsive to MCP-1, but lost their responsiveness as early as 24 h after in vitro culture. In contrast, the calcium flux induced by MIP-1 was the opposite: fresh monocytes showed no significant Ca²⁺ flux to MIP-1 which, however, changed gradually with ongoing differentiation and reached maximal levels in macrophages (Fig. 1B , left panel).

Chemokine receptor expression on monocytes differentiating into macrophages
The above results led us to assume a differentiation-dependent expression of surface-bound receptors. In an attempt to explore the underlying molecular mechanisms, we determined the expression of the chemokine receptors CCR1, CCR2, and CCR5 on the cell surface of maturing monocytes. The strong reduction of the mean fluorescence intensity (MFI) shows that differentiating monocytes markedly down-regulated CCR2 on their surface (Fig. 2A , right panel). The MFI was reduced from 690 units in freshly prepared monocytes to 590 in monocyte-derived macrophages cultured for 48 h (Fig. 2B) . In contrast, CCR1 and CCR5 receptor staining increased continuously with ongoing differentiation and reached the highest values in macrophages (Fig. 2A , left and middle panels). The MFI of CCR1 (550 units) and CCR5 (400 units) in fresh monocytes was up-regulated to 750 and 500 after 48 h of culture (Fig. 2B) .

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Figure 2. Cell surface expression of CCR1, CCR5, and CCR2 during differentiation of monocyte. (A) Monocytes at different stages of differentiation were stained with specific antibodies and analyzed for CCR1, CCR2, and CCR5 expression using FACScan analysis. (B) The time-dependent level of surface expression is displayed as the mean fluorescence intensity (MFI). Data are representative for five separate donors.

Time course of chemokine receptor mRNA expression
To determine whether the changes of receptor density on the cell surface and the functional responsiveness are regulated on the transcriptional level, we examined the expression of chemokine receptor mRNA by using a multiprobe RNase protection assay (Fig. 3 ). Fresh monocytes expressed high levels of CCR2a and CCR2b mRNA. Differentiation into macrophages led to a rapid down-regulation of the CCR2b mRNA, whereas expression of the CCR2a isoform was only weakly affected. In striking contrast to the decreasing CCR2b expression, we observed an up-regulation of CCR1 and CCR5 transcripts. The expression of CCR1 mRNA peaked at 8 h of cultivation and was maintained at high levels. The initially low amount of CCR5 transcripts steadily increased for at least 24 h.

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Figure 3. Chemokine receptor mRNA levels in differentiating monocytes. mRNA levels for chemokine receptors were visualized at different stages of differentiation by RNase protection assay as described in Materials and Methods. One representative analysis out of six independent experiments is shown.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Chemokines play a pivotal role in the regulation of host defense and the recruitment of leukocytes. Extravasation and activation are triggered by binding to chemokine-specific receptors on the surface of the responding cell. Thus, the expression of distinct subsets of chemokines together with the regulated expression of chemokine receptors in a finely tuned manner may be essential for the concerted regulation of inflammatory reactions.

In the present study, we analyzed the chemokine receptor expression of human monocytes and identified a functional and phenotypical switch in the time course of differentiation into macrophages. Monocytes expressing high levels of CCR2b mRNA (Fig. 3) and surface-bound CCR2 protein (Fig. 2 , right panel) showed the strongest biological responsiveness to MCP-1 (Fig. 1A and 1B) . During differentiation, the levels of mRNA and receptor expression decreased and the functional responsiveness to MCP-1 was substantially lost. In contrast, we observed an up-regulation of CCR1 and CCR5 expression (Figs. 2 and 3) that coincided with an increased responsiveness of monocyte-derived macrophages to MIP-1 (Fig. 1 , left and middle panels).

The calcium flux induced by the non-chemokine, but chemotactic, agent N-formyl-methionyl-leucyl-phenylalanine (fMLP) did not significantly change when monocytes differentiated to macrophages (data not shown), indicating a different regulation of receptors binding either chemokines or fMLP. Occasionally, donors showed a transient phase of hyporesponsiveness to MIP-1, which was paralleled by release of endogenous MIP-1, that peaked around 16 h and rapidly declined thereafter (data not shown). However, these donors fully regained their responsiveness to MIP-1, and the values of intracellular calcium concentrations always exceeded those obtained after stimulation of fresh monocytes.

In contrast to the marked down-regulation of CCR2b mRNA, the expression of the alternatively spliced CCR2a transcripts was only weakly affected, indicating a differential regulation of the human MCP-1 receptor types. The different cellular localization of the alternatively spliced CCR2 isoforms [¹⁷ ] may explain this differential regulation. The CCR2b isoform is responsible for the appearance of the receptor on the cell surface and, therefore, essential to mediate MCP-1-induced actions.

A coordinated regulation of chemokine receptor expression and an altered functional responsiveness during differentiation has also been reported for dendritic cells and T cells. Immature dendritic cells have been shown to express the CC chemokine receptors CCR1, CCR2, and CCR5. After stimulation-dependent maturation, the response induced by the respective ligands was lost. However, the differentiation was accompanied by a strong up-regulation of CCR7 mRNA and the mature dendritic cells acquired responsiveness to the CCR7 ligand ELC [¹⁸ , ¹⁹ ]. This process may allow the dendritic cells to migrate from tissue via the lymphatic vessels into the lymph nodes. On naive T cells, the expression of CCR7 and CXCR4 were down-regulated, whereas CCR3, CCR5, and CXCR3 expressions were up-regulated after priming and differentiation into memory/effector T cells [²⁰ ]. Upon TCR stimulation these pre-activated memory/effector cells transiently lost CCR1, CCR2, CCR3, CCR5, CCR6, and CXCR3 expression and up-regulated receptors such as CCR7, CCR4, CCR8, and CXCR5, thus enabling the cells to recirculate from tissue into draining lymph nodes [²¹ ].

A previously published report has also demonstrated a progressive decrease of CCR2 mRNA expression during the differentiation of human monocytes, which was associated with a strong reduction of their functional response to MCP-1 and the disappearance of receptor expression on the cell membrane [22]. Our CCR2 expression data fully support these observations, but extend substantially these findings. The down-regulation of CCR2 expression and lowered MCP-1 responsiveness was accompanied by the parallel induction of CCR1 and CCR5, which give rise to an enhanced responsiveness to MIP-1.

In conclusion, we have identified a switch in the responsiveness to chemokines when monocytes differentiate into macrophages that is based on an altered expression of the corresponding receptors. The switch from CCR2 in monocytes to CCR1 and CCR5 in macrophages characterizes the differentiation of monocytes to macrophages and may essentially contribute to the distinct chemokine responsiveness of monocytes and macrophages.

 
This work was supported by grant Sp 395/2-2 from the Deutsche Forschungsgemeinschaft. We thank Timm Greulich for critically reviewing the manuscript.

Received September 11, 2000; accepted September 23, 2000.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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