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*Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany; Division of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Correspondence to Dr. Detlef Schlöndorff, Medizinische Poliklinik der LMU, Pettenkoferstr. 8a, 80336 München, Germany. Phone: 49-89-51603500; Fax: 49-89-51604439;
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Abstract |
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secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune-mediated diseases in general. E-mail: Detlef.Schloendorff@pk-i.med.uni-muenchen.de |
Introduction |
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The immunostimulatory effects of bacterial or viral molecules such as LPS, lipoproteins, peptidoglycans, and RNA/DNA are recognized through the different members of the MyD88-dependent Toll-like receptor (TLR) family (4). It has recently been found that the stimulatory potential of prokaryotic DNA relates to the presence of the unmethylated CpG-dinucleotide, which occurs at high frequency in prokaryotic in contrast to mammalian DNA (5–8). The unmethylated CpG motif is specifically recognized by TLR9, which leads to activation of NF-
B involving the IRAK and TRAF6 cascade (4,9,10). CpG-DNA-TLR9 interaction stimulates B cells, macrophages, and dendritic cells to secrete cytokines, especially Th1-like cytokines such as IL-12 and IL-18 (4,11). Induction of a Th1-type response with CpG-ODN is considered as a promising approach for vaccination strategies, treatment of infections by intracellular pathogens, or diseases characterized by a predominant Th2-type response (12–16).
However, the immunostimulatory potential of prokaryotic or even hypomethylated self-DNA may also affect underlying chronic inflammatory diseases or autoimmunity (17–20), e.g., immune complex GN, as Th1/Th2 balance, macrophage activity, and B cell function contribute to the pathogenesis of renal immune complex disease (21,22). We therefore hypothesized that CpG-DNA would aggravate a preexisting immune complex GN, a hypothesis confirmed by our results. The worsening of glomerular damage was associated with marked macrophage infiltration, a finding also noted by others using CpG-ODN in various disease models (23–25). Further analysis revealed, as a novel mechanism, that CpG-DNA-TLR9 interaction induced chemokine and chemokine receptor expression in macrophages. We therefore conclude that CpG-DNA can aggravate immune complex GN via multiple pathways, including increased chemokine and chemokine receptor expression vby macrophages supporting further macrophage infiltration into the glomerulus. These data may also have important implications for the understanding of infection-associated exacerbations of autoimmune diseases in general.
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Material and Methods |
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To assess the renal distribution of injected CpG-ODN, 40 µg of 3'-rhodamine-labeled CpG-ODN (TIB Molbiol) were injected intraperitoneally into Balb/c mice with and without HAF-GN on day 14. Serum samples and renal tissue were collected 4 h later and subjected to further analysis as described below.
Evaluation of Immune Complex Glomerulonephritis
Blood samples were collected from each animal at the end of the study by bleeding from the retro-orbital venous plexus under general anesthesia with inhaled ether. Spot urine samples were collected from each animal at the end of the study, and urine albumin concentration was measured using a commercial mouse albumin ELISA quantitation kit (Bethyl Laboratories, Montgomery, TX). The immune response to the injected antigen was assessed by measuring anti-HAF titers by an ELISA method as described previously (26). The following antibodies were used as detection antibodies: total mIg, P260 (Dako, Hamburg, Germany); mIgG1 (Pharmingen, Hamburg, Germany); mIgG2a and mIgM (Dianova, Hamburg, Germany).
Light and Electron Microscopical Evaluation
From each mouse, the left kidney was used for histologic assessment. Two-micrometer-thick paraffin-embedded sections were cut and stained with periodic acid-Schiff reagent. The severity of the renal lesions was graded by two blinded investigators using the indices for activity and chronicity as described for human proliferative lupus nephritis (27). A small piece of cortical tissue from the lower kidney pole was fixed in glutaraldehyde and embedded in araldite for EM analysis as described (26).
Immunofluorescence
The distribution of rhodamine-labeled ODN was assessed on frozen sections after acetone fixation. HAF deposits were detected on frozen sections by a FITC-conjugated anti-horse ferritin antibody (1:100; Jackson ImmunoResearch, West Grove, PA) and complement factor-3 (C3) by a FITC-conjugated anti mouse C3 antibody (ICN Pharmaceuticals, Frankfurt, Germany). Thirty glomeruli were counted from each section, and signals were assessed by a semiquantitative score: 0 = no signal, 1 = low signal intensity, 2 = moderate signal, 3 = strong signal.
Immunohistology
Paraffin-embedded sections were deparaffinized and microwave-treated for antigen retrieval. For staining of immunoglobulins, acetone-fixed frozen sections were used as described (26). The following rat and rabbit antibodies were used as primary antibodies: anti-Mac2 (macrophages, Pharmingen, 1:50), anti-CD3 (lymphocytes, Pharmingen, 1:100), anti-Ki-67 (cell proliferation, Dianova, rabbit, 1:100), mIgG1 (Pharmingen, 1:100), mIgG2a (Dianova, 1:100), and mIgM (Dianova 1:100). Glomerular cells were counted in 15 cortical glomeruli per section. Scoring of mesangial IgG depositis was performed as described above.
Measurement of Interferon (IFN)- Production by Splenocytes
Spleens were removed under aseptic conditions and placed in RPMI 1640 10% fetal calf serum on ice. After manual dissection, centrifugation, and an additional wash step, single cell suspensions (4 x 106 cells/ml) were incubated in RPMI 1640 (Biochrom KG, Berlin, Germany) plus 10% fetal calf serum and 10 µg/ml phytohemagglutinin at 37°C, 5% CO2. Culture supernatants were removed after 48 h, and IFN- concentrations were determined with an ELISA kit (Pharmingen).
RNase Protection Assay
From each animal, the right kidney was snap frozen in liquid nitrogen and total RNA was prepared as described (26). Multi-probe template sets for mouse CC chemokines (mCK-5) and mouse CC chemokine receptors (mCR-5, Pharmingen, San Diego, CA) were performed as described (26). Finally, gels were exposed on phosphor screens of a Storm 840 PhosphorImager (Molecular Dynamics, Sunnyvale, CA). Bands were quantified using the ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
In Vitro Studies with Macrophage-Like J774 Cells and Mesangial Cells
For analysis of potential effects of ODN on murine macrophages or intrinsic glomerular cells, the following cell lines were used. J774 cells (American Type Culture Collection, Rockville, MD) were grown in RPMI 1640 containing 1mM HEPES, 10% heat-inactivated bovine serum, and 1% penicillin-streptomycin. A murine mesangial cell line was maintained in Dulbecco modified Eagle’s medium (DMEM; Biochrom KG, Berlin, Germany) supplemented with 5% bovine serum (Serum Supreme; BioWhittaker, Walkersville, MD) and 1% penicillin-streptomycin 100 U/ml and 100 µg/ml (Biochrom KG, Berlin, Germany) as described (28). J774.1 cells and mesangial cells were incubated for 6 and 24 h with 3 µM of CpG-ODN, GpC-ODN, or standard medium without supplements. After stimulation, cells were harvested by trypsinization and total RNA was prepared as above.
PCR for TLR9
Total RNA was treated with DNase I (Qiagen, Hilden, Germany) and reverse transcribed to cDNA using Superscript reverse transcriptase (Qiagen). Negative control samples were prepared by performing the latter reaction in the absence of reverse transcriptase (RT- control). cDNA was analyzed by performing PCR using an initial cycle of 62° for 45 s and 94°C for 45 s, followed by 30 cycles of 94°C and 72°C for 45 s each. The following primers were used to detect the corresponding murine gene products: TLR9 (f, 5-AGG CTG TCA ATG GCT CTC AGT T-3; r, 5-TGA ACG ATT TCC AGT GGT ACA AGT-3); 
-actin (f, 5-AGC AGC CGT GGC CAT CTC TTG CTC GAA GTC-3; r, 5-AAC CGC GAG AAG ATG ACC CAG ATC ATG TTT-3). Total spleen cDNA was used as a positive control for TLR9 expression.
Real-Time Quantitative RT-PCR
RNA preparation and real-time RT-PCR was performed as described (26). Controls consisting of ddH2O were negative for target and the housekeeper 16S rRNA. The following oligonucleotide primers (300 nM) and probes (100 nM) were used. Murine CCR1: sense5'-TTAGCTTCCATGCCTGCCTTATA-3', antisense 5'-TCCACTGCTTCAGGCTCTTGT-3', internal fluorescence-labeled probe (FAM) 5'-ACTCACCGTACCTGTAGCCCTCATTTCCC-3'; murine CCR2: sense 5'-CCTTGGGAATGAGTAACTGTGTGA-3'; antisense 5'-ACAAAGGCATAAATG-ACAGGATTAATG-3', FAM 5'-TGACAAGCACTTAGACCAGGCCATGCA-3'; murine CCR5: sense 5'-CAAGACAATCCTGATCGTGCAA-3', antisense 5'-TCCTACTCCCAAGCTGCATA-GAA-3', FAM 5'-TCTATACCCGATCCACAGGAG-AACATGAAGTTT-3'; CCR5 specificity of primers and probe were tested on CCR plasmids. The murine 16S rRNA probe was obtained as predeveloped probe from PE Biosystems, Weiterstadt, Germany.
Statistical Analyses
Data are expressed as mean ± SD. Comparison of groups was performed using univariate ANOVA, and post hoc Bonferroni correction was used for multiple comparisons. Paired Student‘s t test was used for the comparison of single groups (IFN- data). A value of P < 0.05 was considered to indicate statistical significance.
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Results |
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CpG-ODN but Not Control GpC-ODN Aggravate HAF-GN
In mice with HAF-GN, two injections with CpG-ODN markedly aggravated albuminuria (Figure 3). This finding correlated with an aggravation of histopathologic markers of glomerulonephritis, such as increased mesangial expansion and glomerular proliferation (as judged by Ki-67–positive cells), capillary thrombosis, and glomerulosclerosis (Table 1; Figure 2). Renal damage was restricted to glomeruli, and changes of the tubulointerstitium were not observed. The extent of renal damage is illustrated by an increase of the activity and chronicity index for proliferative GN. In contrast, injection of the control GpC-ODN in HAF-GN mice did not aggravate the glomerular disease (Figure 3). Mesangial HAF and C3 staining was not affected by CpG-ODN treatment.
Ultrastructurally in glomeruli of HAF-GN mice given the CpG-ODN, electron-dense deposits of varying size could be seen in the mesangium, were more numerous than in HAF-GN mice given the GpC-ODN, and could also be observed in a subendothelial distribution in glomerular capillaries (Figure 4). In HAF-GN mice injected with control-ODN, capillaries were frequently patent but with CpG-ODN macrophages with lysosomes, and fat droplets obstructed the majority of capillaries and were also present in large amounts within the mesangium (Figure 4). CpG-ODN-treated mice had diffuse podocyte foot process effacement compared with GpC-ODN–treated mice that showed normal to plumb podocyte foot processes (Figure 4).
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CpG-ODN Induce an Immune Response of the Th1-Type
To characterize the Th1/Th2 balance during HAF-GN, we measured serum titers of HAF-specific IgG1 and IgG2a as a marker of B cell response. The IgG subclasses within mesangial immune deposits were also assessed by immunohistochemistry. In addition, splenocyte IFN- secretion was measured as a marker of T cell polarization. CpG-ODN–treated mice had an increase of HAF-specific serum IgG2a and of mesangial IgG2a deposits as compared with GpC-ODN and saline controls (Table 1; Figure 1). In contrast, the serum titers of total HAF-specific IgG1 and mesangial IgG1 deposits were comparable in all groups of mice with HAF-GN. CpG-ODN also increased IFN- production of isolated splenocytes compared with GpC-ODN and saline controls (HAF+CpG, 404 ± 231 pg/ml versus HAF+GpC, 52 ± 57 pg/ml; P < 0.002). GpC-ODN did not affect total serum IgG titers compared with saline-injected HAF-GN mice. In contrast, the trend toward increased serum IgM titers in CpG-ODN–treated HAF-GN mice did not reach statistical significance (Table 1). Together, these data indicate that CpG-ODN specifically induced an immune response of the Th1-type in the Balb/c mice with HAF-GN.
CpG-ODN Treatment Stimulates Renal Chemokine and Chemokine Receptor Expression
To examine whether the increased amount of glomerular macrophages in Balb/c mice correlated with local chemokine expression, we performed RNase protection assays with mRNA isolated from the affected kidneys. At 14 d, HAF-GN kidneys contained low levels of CC-chemokine mRNAs for CCL2/MCP-1, CCL3/MIP-1
, and CXCL1/MIP-2 as reported previously (Figure 5A; reference 26). Treatment with CpG-ODN significantly increased renal chemokine mRNA expression of the chemokines CCL5/RANTES, CCL3/MIP-1, CCL4/MIP-1, CXCL1/MIP-2, and CCL2/MCP-1. GpC-ODN had no significant effect on chemokine mRNA expression in kidneys with HAF-GN (Figure 5A).
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TLR9 Is Expressed in the Kidney with HAF-GN but Not in Normal Mice
CpG-DNA requires interaction with TLR9 to mediate its stimulatory effects. RT-PCR for TLR9 using total kidney RNA from mice of the various groups revealed that TLR9 was not expressed in renal tissue from healthy mice (Figure 5C). At day 7, of HAF-GN, the time just before the first administration of CpG-DNA, kidneys of Balb/c mice with HAF-GN expressed TLR9. At day 14, kidneys from all groups of mice with HAF-GN also expressed the TLR9 irrespective of ODN injections (Figure 5C). Thus induction of HAF-GN resulted in a positive signal for TLR9 in the affected kidneys irrespective of CpG-ODN administration.
Macrophages but Not Mesangial Cells Express the CpG-DNA Receptor TLR9
In HAF-GN, the glomerular hypercellularity consisted of infiltrating macrophages and proliferation of mesangial cells. To evaluate which glomerular cell type contributes to the TLR9 expression during HAF-GN, we studied the expression of TLR9 in established cell lines of murine macrophages and mesangial cells. RNA isolates of J774 cells and mesangial cells. J774 cells constitutively expressed TLR9 as determined by RT-PCR (Figure 6). In contrast, TLR9 was not detected in mesangial cells, indicating that the TLR9 expression seen in kidney isolates probably originated from infiltrating macrophages (Figure 6).
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, CCL4/MIP-1, CXCL1/MIP-2, and CCL2/MCP-1 (Figure 7). Incubation with CpG-ODN for 6 and 24 h markedly increased the mRNA expression of all of the above chemokines and in addition CCL5/RANTES (Figure 7). GpC-ODN did not consistently influence chemokine mRNA levels in J774 cells. Under basal culture conditions, J774 cells showed constitutive levels of mRNA for the chemokine receptors CCR1 and CCR5, which were increased by 2.3-fold and 2.9-fold, respectively, in the presence of CpG-ODN (Figure 7). Incubation with the GpC-ODN had no effect on chemokine receptor expression.
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CpG-ODN Aggravate HAF-GN in Balb/c Mice in a Sequence-Specific Manner
Our observation that the aggravation of HAF-GN depends on the CpG dinucleotide sequence underlines the importance of this motif for the immunostimulatory actions of DNA, which was identified as the trigger sequence in 1995 by Krieg et al. (6). CpG-DNA mediates its effects exclusively via TLR9 (10). Although there are obvious similarities to the activation of immune cells by prokaryotic LPS, lipoproteins, and peptidoglycans, these are mediated by other members of the TLR family (4,30,31). In contrast to the toxic effects of the latter antigens on naïve animals or humans, our present studies and previous ones by others demonstrate that CpG-DNA alone does not affect healthy mice (10). In extension of the concept of an innate, nonspecific (Th1) response to unmethylated CpG-DNA, the recognition of CpG-DNA-IgG complexes by crosslinking of B cell surface IgM receptors and TLR9 has been shown to stimulate DNA-specific IgG and IgM secretion as a link to adaptive immunity (1,32). Although the activation of both innate and adaptive systems may support pathogen clearance (5), both responses may also lead to unfavorable effects in autoimmunity and chronic inflammatory disease (4). The clinical observation that infections can exacerbate chronic inflammation in humans, and recent findings from in vivo models support this hypothesis. For example, CpG-ODN aggravated rat experimental allergic encephalomyelitis and collagen-induced arthritis in DBA/1 LacJ mice, two disease models that, as HAF-GN, rely on antigen-induced immune responses (15,33).
CpG-ODN Induce an Immune Response of the Th1-Type during HAF-GN
CpG-ODN are known stimulators of an Th1-type immune response by induction of IL-12 and IFN- that direct T cell differentiation and switch of IgG subclasses (11). This type of immune response is a major strategy of the innate immune system to direct acquired immune responses to control extracellular and intracellular pathogens (15,16,29). However, induction of a Th1 response may significantly alter the course of underlying inflammatory disease states toward either resolution or progression, depending on the disease. For example, CpG-ODN-induced Th1-shift correlated with a marked improvement of ragweed-induced asthma in Balb/c mice (34) and, in contrast, aggravated collagen-induced arthritis in DBA/1 LacJ mice (18). Most of the data on the role of the Th1/Th2 balance in renal disease have been derived from the models of nephrotoxic serum nephritis and lupus nephritis in MRLlpr/lpr mice (20). In Balb/c mice prone to a predominant Th2 response, administration of the Th1 cytokine IL-12 induced marked glomerular crescent formation during nephrotoxic serum nephritis (35). Similarly, daily administration of IL-12 to MRLlpr/lpr mice aggravated glomerular lesions and proteinuria (36). In our experiments with HAF-GN in Balb/c mice, the administration of CpG-DNA induced a Th1-type immune response as demonstrated by increased IFN- secretion by splenocytes and an IgG subclass switch toward enhanced IgG2a levels. We therefore conclude from our data that one mechanism by which CpG-DNA can aggravate the course of preexisting immune complex GN would be by favoring an immune response of the Th1-type. The CpG-ODN could be of infectious or endogenous origin, e.g., in lupus nephritis. Thus this mechanism may be relevant to both immune and autoimmune-associated glomerular diseases.
CpG-ODN Induce the Infiltration and Activation of Macrophages in the Glomerulus
CpG-ODN have been shown to induce macrophage activation and recruitment to the site of injection in a variety of animal models (23,24). CpG-ODN given to sensitized SCID beige mice lacking T cells, B cells, and NK cells induced lethal toxic shock via macrophage-derived TNF- secretion (8). CpG-ODN activated macrophages via TLR9 to secrete a variety of proinflammatory mediators such as IL-1, IL-12, TNF-, CD80, and CD86 as well as CC-chemokines (6,10,11,37,38). HAF-GN is a model that largely depends on glomerular macrophage accumulation (26). We observed that CpG-ODN administration aggravated renal damage and albuminuria in HAF-GN, which was associated with increased amounts of glomerular macrophages. We therefore questioned whether CpG-ODN altered local chemokine production. In fact, we found enhanced mRNA levels for several CC-chemokines specifically after CpG-ODN administration in kidneys with HAF-GN. Furthermore, while normal kidneys had undetectable levels of mRNA for TLR9, all kidneys with HAF-GN showed positive levels of TLR9 mRNA. As HAF-GN is characterized by mesangial cell proliferation and macrophage infiltration, we examined these cells as potential sources of mRNA for TLR9, CC-chemokines, and chemokine receptors. Using established cell lines of murine macrophages and mesangial cells, we found that J774 cells but not mesangial cells expressed the CpG-DNA receptor TLR9. In addition in J774 cells but not in mesangial cells, CpG-ODN markedly induce the mRNA expression of CC-chemokines and, as a novel finding, the respective chemokine receptors CCR1 and CCR5. We have previously demonstrated the role of the glomerular expression of CCL5/RANTES for the infiltration of CCR1- and CCR5-positive macrophages and lymphocytes in HAF-GN (26,39). Thus the CpG-ODN-induced increase of glomerular macrophages could be a result of CpG-ODN-induced enhancement of chemokine and chemokine receptor expression, especially macrophages with an increase of an intraglomerular amplification loop. In this context, it is of special interest that labeled CpG-ODN colocalize with the glomerular immune deposits in the mice with HAF-GN, whereas no glomerular localization of CpG-ODN occurs in normal kidneys. The colocalization of the immune deposits and the injected CpG-ODN could even indicate a local mechanism of macrophage activation in the glomeruli, a hypothesis deserving further studies. Taken together CpG-ODN triggered chemokine and chemokine receptor expression on macrophages, which results in increased macrophage infiltration into the glomerulus, contributing to further glomerular damage and proteinuria during GN (21).
In summary, unmethylated CpG-ODN aggravated immune complex GN. The immunostimulatory and TLR9-mediated mechanisms of CpG-DNA include the induction of a Th1 response and, as a novel mechanism, the selective induction of chemokine and chemokine receptor expression on macrophages, contributing to their enhanced recruitment to the site of injury. On the basis of these findings, we speculate that bacterial DNA containing the unmethylated CpG motif released during infection or autoimmune diseases may represent a formerly unrecognized trigger for flares in immune-mediated forms of GN, thus contributing to progressive renal dysfunction.
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