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* Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany;
Max Delbrück Center for Molecular Medicine, Berlin, Germany; and
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chemokines and chemokine receptors have been further classified according to their function and regulation of expression. Some chemokines are important in the control of inflammatory processes (3). During inflammatory glomerular disease or transplant rejection, chemokines such as monocyte chemoattractant protein (MCP)3-1/CCL2 and RANTES/CCL5 are up-regulated by both intrinsic renal cells and infiltrating leukocytes (4).
An additional subgroup of chemokines is involved in homeostasis of lymphocyte and dendritic cell trafficking during immune surveillance. The regulated expression of the chemokine secondary lymphoid tissue chemokine (SLC/CCL21) and its corresponding receptor, CCR7, represents a prototypic model for chemokine/chemokine receptor functions in normal lymphoid tissue (5, 6). SLC/CCL21 is constitutively produced by high endothelial venules and by stromal cells within T cell zones of lymphoid organs. CCR7 is present on T cell subpopulations (7). CCR7 is up-regulated by maturing dendritic cells and helps direct the dendritic cells to secondary lymphoid organs (8). A spontaneous mouse line lacking SLC/CCL21 (9) and CCR7 knockout mice (10) shows impaired homing of T cells into lymph nodes and Peyer’s patches within the small intestine.
The biology of chemokines and chemokine receptors has become more complex with the demonstration of functional chemokine receptor expression on nonhematopoietic tissues. For example, endothelial cells (11), epithelial cells (12), microglial cells (13), neurons (14), and mesangial cells (MC) (15, 16) have been shown to express chemokine receptors. The role of chemokine receptor expression by nonhematopoietic cells is not completely understood, but it is thought to be important in angiogenesis and tissue remodeling, e.g., during atherosclerosis, wound healing, and tumor metastasis (17, 18).
MC are involved in local immune regulation within the glomerulus (19). We have previously described the inducible expression of the chemokine receptor CCR1 by human MC (15). In this work we describe the functional and constitutive expression of CCR7 on human MC. Interestingly, the CCR7 ligand SLC/CCL21 is constitutively expressed by glomerular podocytes in human kidney. Effects of SLC/CCL21 on mesangial migration, proliferation, and cell death were found, suggesting a potential homeostatic function for this chemokine/chemokine receptor pair in the glomerulus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human tissue was used following the guidelines of the Ethics Committee of the Medical Faculty of the University of Heidelberg (Heidelberg, Germany). Adult kidneys removed for reflux nephropathy were used to establish specific staining protocols for each Ab. Immunohistochemistry was conducted on frozen tissue sections of normal human kidney essentially as described previously (20) using an avidin biotinylated enzyme complex method. Staining for CCR7 was performed using a specific mouse mAb, as described (21). mAbs specific for human SLC/CCL21 and CD31/platelet endothelial cell adhesion molecule (PECAM)-1 were obtained from R&D Systems (Wiesbaden, Germany). Control experiments entailed immunohistology with nonimmune mouse or rat IgG, respectively, and without primary Ab. Negative controls for the avidin biotinylated enzyme complex stain generated with nonimmune control Ab and without primary Ab did not show any staining (data not shown).
Cell culture conditions for human MC
Immortalized human MC were grown as described previously
(15). This MC line showed no dedifferentiation within
100 passages during a 36-mo cultivation period. Furthermore, it was
characterized for antigenic markers typically expressed by MC in vivo
and in vitro and is known to have a specific expression pattern for
chemokines and the chemokine receptor CCR1 identical to primary human
MC (15). For all experiments, passages 51–65 were used.
Different preparations of primary human MC served as controls and were
cultured as previously published (19).
Stimulation of human MC and RNA preparation
Human MC were stimulated for 4–96 h with human rTNF-
(20
ng/ml), human rIL-1
(2 ng/ml), and human rIFN-
(10 ng/ml), either
alone or in combination. Additional stimuli tested included TGF--1,
-2, and -3, IL-4, IL-12, RANTES/CCL5, MCP-1/CCL2, eotaxin/CCL11,
monokine induced by IFN-/CXCL9, IFN--inducible
protein-10/CXCL10, and SLC/CCL21 (all from R&D Systems). Control cells
were kept under standard conditions. Cells were harvested by
trypsinization and total RNA was prepared as described
(22).
RT-PCR analysis
Semiquantitative PCR analysis was done as described (15). For real-time quantitative RT-PCR, 2 µg of isolated total RNA underwent random primed reverse transcription using a modified Moloney murine leukemia virus reverse transcriptase (Superscript; Life Technologies, Karlsruhe, Germany). In parallel, 2-µg aliquots were processed without reverse transcription to control for contaminating genomic DNA. Glomeruli were obtained from unaffected kidney compartments from tumor nephrectomies by manual microdissection. Microdissection was verified by demonstration of a podocyte-specific gene (Wilms-tumor gene-1) expressed specifically within the glomerular compartment. Real time RT-PCR was performed on a TaqMan ABI 7700 Sequence Detection System (PE Applied Biosystems, Weiterstadt, Germany). Thermal cycler conditions contained holds at 50°C for 2 min and 95°C for 10 min followed by 40 cycles of 95°C for 15 s and 60°C for 60 s. GAPDH was used as reference gene. All controls consisting of ddH2O were negative for target and housekeeper.
The following oligonucleotide primers (300 nM) and probes (100 nM) were used: human CCR7 (GenBank accession no. NM 001838; bp 816–878) sense (5'-GAGGCCCAGAGGATCGCT-3') and antisense (5'-ACTTGGAGTTGATGATTTGCGG-3'), internal fluorescence-labeled probe (FAM) (5'-CAACCACATCAAGCTGTCGGGCAG-3'), human SLC/CCL21 (GenBank accession no. AB 002409; bp 194–275) sense (5'-CGCAGCTACCGGAAGCAG-3') and antisense (5'-CTGCCTGAGAGCGCTTGC-3'), and probe (FAM) (5'-CTCCATCCCAGCTATCCTGTTCTTGCC-3'). SLC primer pairs are intron-spanning leading to exclusive amplification of cDNA. For CCR7 no cDNA-specific primers were available. Therefore, non-reverse-transcribed samples were analyzed in parallel to control for contaminating genomic DNA. All primers and probes were obtained from PE Applied Biosystems.
RNase protection assay
Template sets for human chemokine receptors for use in RNase protection assays were obtained from BD PharMingen (San Diego, CA). RNase protection assays were performed according to the manufacturer’s instructions using 20 µg of total RNA from human MC to analyze the expression of CCR7 mRNA. Equal amounts of tRNA were used as control to exclude incomplete digestion of the probes. After drying, gels were exposed on phosphor screens for use with a Storm 840 PhosphorImager (Molecular Dynamics, Sunnyvale, CA).
FACS analysis
For FACS analysis human MC were detached with PBS/10 mM EDTA (pH 8) and stained for CCR7 using a specific mouse mAb and a two-step amplification method as described previously (21). The CCR7 signal was analyzed using a FACScan flow cytometer (BD Biosciences, Mountain View, CA). Appropriate IgG isotype preparations were used to control for unspecific staining.
Proliferation assays
To assess the proliferative activity of human MC, MTT (Sigma-Aldrich, Deisenhofen, Germany) assays were performed (23). Aliquots of 20 x 103 cells in 100 µl medium were cultured in 96-well microtiter plates for 24 h under standard conditions to yield firmly attached and stably growing cells. After discarding the supernatants, 50 µl of medium containing chemokines and/or cytokines were added and the cells were incubated from 24 to 72 h. Then 50 µl of a 1 mg/ml solution of MTT were added. After a 3-h incubation at 37°C formazan crystals were dissolved by addition 50 µl isopropanol. Absorbance was measured at 550 nm using a DYNATECH MR7000 ELISA reader. For each experiment at least six wells were analyzed per experimental condition and time point.
Chemotaxis assays
In chemotaxis assays 2 x 105 MC per well were plated onto Transwell filter inserts (8-µm pore size; Costar, Cambridge, MA) coated with fibronectin (Boehringer Mannheim, Mannheim, Germany). Assay medium consisted of DMEM, 0.1% BSA (Sigma-Aldrich), and 10 mM HEPES (Life Technologies). After a 3-h incubation at 37°C, chemotactic factors (diluted in assay medium) were added to 12-well tissue culture plates. Transwells were inserted to the wells and then incubated for 4 h. Cells that had migrated to the bottom of the filter and/or the bottom chamber were collected by trypsinization and counted using flow cytometry as described previously (15).
Cell death assays
Apoptosis of MC was induced by Fas/CD95 ligation according to
the method of Gonzalez et al. (24) after starvation of the
cells in serum-free medium and prestimulation with IFN-
to induce Fas/CD95 surface expression. For analysis of chemokine
effects, cells were pretreated with 250 ng/ml SLC/CCL21 before adding
the activating anti-human Fas Ab (Biomol, Hamburg, Germany).
Three different assays were used to study apoptosis. Flow cytometric
cell cycle analysis using propidium iodide staining was performed as
described (25). For visualization of chromatin
fragmentation, MC were seeded on chamber slides (Nunc,
Wiesbaden, Germany). After treatment with test substances cells were
fixed with ethanol and stained with the nuclear dye Hoechst 33258
(Hoechst, Bad Soden, Germany) 5 µmol/ml. The percentage of apoptotic
cells was determined by immunofluorescence microscopy, counting nuclei
with condensed or fragmented chromatin. Three independent experiments
were performed; at least 300 cells were analyzed per condition.
Counting was performed in a blinded manner by two investigators. For
measurement of caspase-3 activity (26), a commercial assay
(R&D Systems) was used according to the manufacturer’s specifications.
After induction of apoptosis as described above, the human MC were
lysed and caspase-3-specific proteolytic activity was quantitated
spectrophotometrically. Three experiments were done analyzing
duplicates for any experimental condition.
"Wound healing" experiments
Scratch assays (27, 28) were performed as an in vitro model for "wound healing." Human MC were grown under standard conditions in six-well tissue culture dishes until confluent. At the time point 0 h the cell monolayer was scratched in a standardized manner with a plastic spatulum to create cell-free areas (2 mm in width) in each well. Afterward the cell culture medium was replaced by test medium containing either standard medium or medium supplemented with human rSLC/CCL21 (250 ng/ml). The "wounds" were observed at 6-h intervals for 48 h by phase contrast microscopy and documented by photography. Each experiment was performed in duplicate analyzing at least four scratches per well.
Statistical analysis
Values are provided as mean ± SEM. Statistical analysis
was performed by unpaired t test. Significant differences
(see
Figs. 4–6
) are indicated for p values <0.05 (*) or
0.01 (**), respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Representative immunohistochemical sections of human kidney
stained with an anti-SLC/CCL21 Ab are shown in Fig. 1A. Normal adult kidney showed
a strong staining in the periphery of capillaries in a podocyte-like
pattern. Staining for the corresponding receptor CCR7 was seen
primarily in the mesangium but also in medial artery smooth muscle
cells (Fig. 1B). Expression of SLC/CCL21 and/or CCR7 by
glomerular endothelial cells could be excluded by a specific
endothelial counterstain (CD31/PECAM-1). Data shown in Fig. 1 are
representative for kidney tissue prepared from seven adult individuals
of both female and male gender.
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The immunohistochemistry suggested a constitutive expression of
SLC/CCL21 by normal human podocytes. Because differentiated human
podocyte cell lines are not available, the expression of SLC/CCL21 was
evaluated in human glomeruli isolated from normal adult kidney using
manual microdissection. Real-time PCR analysis of the microdissected
glomeruli revealed expression of SLC/CCL21 mRNA (Fig. 2). A positive signal for the Wilms-tumor
gene-1 served as control for the presence of podocyte-specific
transcripts within this RNA preparation. Sequencing of the PCR product
proved the specificity of glomerular SLC/CCL21 mRNA expression (data
not shown). Cultured human MC and human microvascular endothelial cells
failed to express SLC/CCL21 mRNA, suggesting glomerular epithelial
cells as the source of SLC/CCL21 mRNA (data not shown).
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Because glomerular staining for CCR7 resulted in a mesangial
pattern, we examined cultured human MC for expression of CCR7. RNA was
prepared from cells growing under standard conditions as well as from
cells that had been stimulated with a combination of the cytokines
TNF-, IL-1, and IFN- to simulate a proinflammatory situation.
By RT-PCR, specific products for CCR7 mRNA were amplified from both
unstimulated and stimulated cells. Equivalent results were obtained
with immortalized MC and three different preparations of primary
human MC (Fig. 3, A and
B). To confirm and quantitate the CCR7 expression, RNase
protection assays were performed. A constitutive expression of CCR7 was
found analogous to the RT-PCR experiments (Fig. 3C).
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, IL-1, IL-4, IL-5, IL-10, IL-12, TNF-, TGF-1,
TGF-2, and TGF-3), or chemokines (MCP-1/CCL2, RANTES/CCL5,
eotaxin/CCL11, ELC/CCL19, and SLC/CCL21) from 4 to 96 h. No
significant modulation of CCR7 mRNA expression was found under any of
these conditions (data not shown).
To confirm expression of CCR7 protein on human MC, FACS analysis was
conducted with mAbs specifically directed against this receptor
(10). As demonstrated in Fig. 3
D, the human MC
line showed a low but reproducible staining for CCR7. Consistent with
the mRNA data, the amount of receptor detected by flow cytometry did
not differ when MC cells were stimulated with cytokines (data not
shown). Primary human MC also showed a comparable staining by FACS
analysis for CCR7 (Fig. 3E).
Migratory activity of human MC upon stimulation with SLC/CCL21
To demonstrate that CCR7 mediates MC chemotaxis, migration assays
were performed using a Transwell filter system. SLC/CCL21 induced a
directed migration of human MC in a dose-dependent fashion (Fig. 4). Comparable results were obtained in
three independent sets of experiments, each conducted in
triplicate.
SLC/CCL21 induces proliferation of human MC
CCR7 activation has an influence on the proliferative activity of
MC. As shown in Fig. 5A,
stimulation with the CCR7 ligand SLC/CCL21 increased
proliferation of human MC in a dose-dependent manner in a range from 10
to 250 ng/ml. To determine optimal stimulation time, human MC were
incubated with SLC/CCL21 up to 72 h. The highest pro-proliferative
effect of SLC/CCL21 was seen when human MC were stimulated for 48
h (Fig. 5B).
CCR7 signaling promotes MC survival in cell death assays
The potential role of CCR7 for MC survival was studied using
Fas/CD95-mediated cell death assays. Three methods were used to study
the influence of SLC on MC apoptosis: cell cycle analysis, Hoechst
staining, and caspase-3 activity. Cell cycle analysis revealed a
background of 7.8 ± 0.6% apoptotic cells under normal
conditions. After serum starvation and IFN- stimulation human MC
expressed surface Fas/CD95 (data not shown), and 24.5 ± 3.7% of
the cells belonged to a population with a subG1
DNA content (Fig. 6A). Fas
ligation increased the amount of MC displaying a
subG1 DNA content to 52.4 ± 3%, consistent
with a marked increase in apoptosis (Fig. 6B). When MC were
prestimulated with SLC/CCL21 before induction of cell death the
percentage of apoptotic cells was reduced markedly to 30.8 ±
4.6% (Fig. 6C). Staining with Hoechst dye was used to
visualize cells with fragmented chromatin. Under control conditions
10.7 ± 1.9% of the cells were found to be apoptotic, and after
serum starvation and IFN- stimulation 16.5 ± 4.5% of the
cells were found to be apoptotic. Subsequent Fas ligation induced
apoptosis in 45.2 ± 5.8% of human MC. Prestimulation with
SLC/CCL21 reduced Fas-induced cell death effectively to 20.3 ±
7.6% (Fig. 6D). In addition, SLC/CCL21 affected activation
of caspases. Caspase-3 activity was found to be increased 2.8-fold upon
Fas ligation of MC compared with control conditions. Coincubation with
SLC/CCL21 reduced caspase-3 activity significantly (Fig. 6E).
SLC/CCL21 influences "wound closure" in an in vitro injury model
Finally, signaling through CCR7 was tested in an in vitro "wound
healing" model system that requires both migration and proliferation
of cells. Defined lesions were generated in subconfluent layers of
human MC and the repopulation of denuded areas was studied. Under
standard conditions no relevant change of the gap was apparent 12
h after inducing the lesion. After 24 h the gap started to close
but was still visible at 48 h (Fig. 7, left panels). In contrast,
upon addition of SLC/CCL21 accelerated wound closure was already
noticeable after 12 h. At 24 h the lesions were almost closed
and at 48 h the previously cell-free areas were completely
repopulated (Fig. 7, right panels).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to proliferation, the directed migration of cells is necessary for tissue remodeling after injury. In vitro migratory activity of MC has been demonstrated in response to growth factors (31) and angiotensin II (32). During embryonal glomerulogenesis MC migration from the vascular pole into the glomerulus is thought to represent an important step (33, 34). In a rat nephritis model Hugo et al. (35) demonstrated that proliferation is only one mechanism by which MC repopulate the glomerular space after induction of glomerular damage and mesangiolysis. The second important phenomenon is a directed migration of "reserve" MC from the juxtaglomerular apparatus into the glomeruli. In this context it is possible that the local synthesis of chemokines and activation of their receptors may help control MC migration.
It has been suggested that chemokines and chemokine receptors expressed by intrinsic renal cells play a role in kidney development and in the cellular homeostasis of the adult organ (36). In the present study we analyzed the expression of CCR7 and its ligand secondary lymphoid tissue chemokine (SLC/CCL21) in human renal tissue. Immunohistochemistry of human kidney showed a clear staining pattern for CCR7 on MC and SLC/CCL21 on podocytes. These findings were confirmed in cultured cells and isolated glomeruli. Functional assays revealed an influence of SLC/CCL21 on mesangial migration, proliferation, cell death, and in vitro "wound healing." Interestingly, the positive influence of SLC/CCL21 on mesangial proliferation is different from the effect on blood cells. The proliferation rate of normal hematopoietic or leukemia progenitor cells was reduced upon stimulation with SLC/CCL21 (37), suggesting differential actions of this chemokine on hematopoietic or nonhematopoietic cells.
In addition to proliferation, tissue homeostasis including that of MC is regulated by apoptosis (38, 39, 40, 41). In this work we describe that SLC/CCL21 acts as an antiapoptotic factor for MC. As the MC is a specialized pericyte, chemokines and their receptors may function to control vascular smooth muscle homeostasis via proliferation and prevention of apoptosis. This novel role of the pair SLC/CCL21 and CCR7 is reminiscent of the regulation of apoptosis via CX3CR1 described by Boehme et al. (13) for brain microglia. Analogous to the protective effect of SLC/CCL21 on MC survival described in this work, the CX3CR1 ligand fractalkine was shown to maintain cell survival and inhibit Fas ligand-induced apoptosis in brain cells. Mediating cell death and survival could be an important function of chemokine/chemokine receptor interaction, especially on nonimmune cells.
The constitutive expression of SLC/CCL21 by podocytes and of CCR7 on MC
is of interest, because other chemokines and chemokine receptors are
generally expressed after cytokine stimulation. For example, we
described the induction of functionally active CCR1 on human MC after
stimulation with a combination of TNF-, IL-1, and IFN-
(15). Furthermore, CCR1 is up-regulated in kidney cortex
of mice with immune complex glomerulonephritis (42).
Romagnani et al. (16) reported mesangial expression of
CXCR3 in biopsies from patients with mesangioproliferative
glomerulonephritis. Therefore, a role for CCR1 and CXCR3 in
inflammatory glomerular disease has been proposed.
In this context a potential mesangial expression of CXCR3 is of special
interest, because in mice this receptor may bind not only
IFN--inducible protein-10/CXCL10 and monokine induced by
IFN-/CXCL9 but also SLC/CCL21 (43). Whether this
also applies to the human system remains in question (44, 45). In any case, in mice SLC/CCL21 generated by podocytes may
bind to both CCR7 and CXCR3. This redundancy of SLC/CCL21 receptors in
mice may also explain why CCR7 knockout mice do not show a glomerular
phenotype.
The finding of a paired expression of a potential growth factor and its receptor on different but adjacent intrinsic glomerular cells as shown in this work is not unique. For example, vascular endothelial growth factor (VEGF), a potent mitogen for endothelial growth (46), is expressed by podocytes (20, 47) while the respective VEGF receptors are expressed on glomerular endothelial cells and MC (48, 49). Proliferation of human MC occurs upon stimulation with recombinant VEGF (49). To this end, SLC/CCL21 could represent a factor that helps regulate the cellular homeostasis between podocytes and MC, including their number, migration, and interaction with the intervening basement membrane.
The complexity and apparent redundancy of chemokine biology provides a high degree of effectiveness and flexibility in vivo. This redundancy may also exist with regard to tissue homeostasis. Although CCR7 knockout mice have no obvious renal phenotype under basal conditions, the significance of the deleted gene during experimental stress will have to be evaluated. Indeed, it has been shown that genes important in renal development and physiology do not always show renal phenotypes in knockout animals (50).
Based on these observations it is tempting to speculate that migration, proliferation, and apoptosis of MC during glomerulogenesis and glomerular injury might be controlled by the local synthesis of chemokines by podocytes with activation of their respective receptors on MC. At present such a role for SLC/CCL21 and CCR7 for a homeostatic balance between podocytes and MC remains an interesting hypothesis deserving further investigation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Detlef Schlöndorff, Medical Policlinic, Ludwig-Maximilians-University, Pettenkoferstrasse 8a, D-80336 Munich, Germany.
E-mail address: sdorff{at}pk-i.med.uni-muenchen.de or Dr. Hermann-Josef Gröne, Department of Cellular and Molecular Pathology, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail address: h.-j.groene{at}dkfz.de
3 Abbreviations used in this paper: MCP, monocyte chemoattractant protein; MC, mesangial cell; VEGF, vascular endothelial growth factor; PECAM, platelet endothelial cell adhesion molecule.
Received for publication September 26, 2001. Accepted for publication February 11, 2002.
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