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    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; IN-VIVO ; MODEL ; DISEASE ; DISTINCT ; MICE ; ACTIVATED MACROPHAGES ; ACTIVATION ; COMPLEX ; CRESCENTIC GLOMERULONEPHRITIS ; INJURIES ; LIGAND ; MESANGIAL CELLS ; MONOCYTE ARREST ; NEPHRITIS ; NITRIC-OXIDE ; RANTES ; RESPONSES
    Abstract: The chemokine CC chemokine ligand (CCL)5/RANTES as well as its respective receptor CCR5 mediate leukocyte infiltration during inflammation and are up-regulated early during the course of glomerulonephritis (GN). We tested the effects of the two CCL5/RANTES blocking analogs, Met-RANTES and amino-oxypentane- RANTES, on the course of horse apoferritin (RAF)induced GN. HAF-injected control mice had proliferative GN with mesangial immune complex deposits of IgG and HAF. Daily i.p. injections of Met-RANTES or amino-oxypentane-RANTES markedly reduced glomerular cell proliferation and glomerular macrophage infiltration, which is usually associated with less glomerular injury and proteinuria in RAF-GN. Surprisingly, however, RAF-GN mice treated with both analogs showed worse disease with mesangiolysis, capillary obstruction, and nephrotic range albuminuria. These findings were associated with an enhancing effect of the CCL5/RANTES analogs on the macrophage activation state, characterized by a distinct morphology and increased inducible NO synthetase expression in vitro and in vivo, but a reduced uptake of apoptotic cells in vivo. The Immoral response and the Th1/Th2 balance in HAF-GN and mesangial cell proliferation in vitro were not affected by the CCL5/RANTES analogs. We conclude that, despite blocking local leukocyte recruitment, chemokine analogs can aggravate some specific disease models, most likely due to interactions with systemic immune reactions, including the removal of apoptotic cells and inducible NO synthetase expression
    Type of Publication: Journal article published
    PubMed ID: 12759447
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; Germany ; human ; DISEASE ; DISEASES ; MICE ; ACTIVATION ; COMPLEX ; MESANGIAL CELLS ; ARTHRITIS ; CELL ACTIVATION ; COMPLEXES ; CUTTING EDGE ; DNA ; IFN-GAMMA ; INFECTION ; kidney ; MACROPHAGES ; MECHANISM ; MESSENGER-RNA ; MESSENGER-RNA EXPRESSION ; MOTIFS ; murine ; OLIGODEOXYNUCLEOTIDES ; RECEPTOR EXPRESSION ; SERA ; TH1 RESPONSES ; TRIGGER
    Abstract: Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma 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
    Type of Publication: Journal article published
    PubMed ID: 12538732
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  • 4
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; MODEL ; SUPPORT ; VOLUME ; TISSUE ; MICE ; INJURIES ; LIGAND ; NEPHRITIS ; RANTES ; kidney ; MACROPHAGES ; murine ; MARKER ; renal ; RAT ; CONTRAST ; INJECTION ; fibroblasts ; treatment ; IDENTIFICATION ; LESIONS ; immunohistochemistry ; MARKERS ; LIGANDS ; RECRUITMENT ; leukocyte ; STRATEGIES ; intravenous ; NEPHROPATHY ; chemokine ; INITIATION ; ANTAGONIST ; inflammation ; INJURY ; FOCAL SEGMENTAL GLOMERULOSCLEROSIS ; CHEMOKINE RECEPTOR ; fibrosis ; PERSISTENT ; INFILTRATION ; MURINE MODEL ; chemokines ; OBSTRUCTIVE NEPHROPATHY ; progressive nephropathy ; receptor blockade ; RENAL-DISEASE
    Abstract: Background. CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis. Methods. Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry. Results. At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and Tlymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment. Conclusion. Blockade of CCR1 substantially reduced interstitial leukocyte accumulation and the subsequent renal fibrosis in a murine model of nephrotic syndrome and FSGS. These findings support a role for CCR1 in interstitial leukocyte recruitment and suggest that CCR1 blockade might be a new therapeutic strategy in progressive nephropathies such as FSGS
    Type of Publication: Journal article published
    PubMed ID: 15569315
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  • 5
    Keywords: CELLS ; IN-VIVO ; ACTIVATION ; INFECTION ; glomerulonephritis ; DOUBLE-STRANDED-RNA ; MIXED CRYOGLOBULINEMIA ; SERUM-LEVELS ; TOLL-LIKE RECEPTOR-3 ; SYSTEMIC VASCULITIS
    Abstract: In hepatitis C virus (HCV) infection, morbidity and mortality often result from extrahepatic disease manifestations. We provide evidence for a role of receptors of the innate immune system in virally induced inflammation of the endothelium in vitro and in vivo. Corresponding to the in vitro finding of an HCV-dependent induction of proinflammatory mediators in endothelial cells, mice treated with poly (I:C) exhibit a significant reduction in leukocyte rolling velocity, an increase in leukocyte adhesion to the vessel wall and an increased extravasation of leukocytes. HCV directly promotes activation, adhesion and infiltration of inflammatory cells into the vessel wall by activation of endothelial viral receptors. Poly (I:C) induces the expression of TLR3 in vivo and hereby allows for amplification of all of the aforementioned responses upon viral infection. Proinflammatory effects of viral RNA are specifically mediated by TLR3 and significantly enhanced by tumor necrosis factor alpha (TNFalpha). HCV-RNA induces the endothelial expression of TNFalpha and TNFalpha receptor subtype 2 and we provide evidence that leucocyte adhesion and transmigration in response to activation of viral RNA receptors seem to depend on expression of functional TNFR2. Our results demonstrate that endothelial cells actively participate in immune mediated vascular inflammation caused by viral infections.
    Type of Publication: Journal article published
    PubMed ID: 25419735
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  • 6
    Abstract: The atypical chemokine receptor 2 (ACKR2), also named D6, regulates local levels of inflammatory chemokines by internalization and degradation. To explore potential anti-inflammatory functions of ACKR2 in glomerulonephritis, we induced autologous nephrotoxic nephritis in C57/BL6 wild-type and Ackr2-deficient mice. Renal ACKR2 expression increased and localized to interstitial lymphatic endothelium during nephritis. At two weeks Ackr2(-/-)mice developed increased albuminuria and urea levels compared to wild-type mice. Histological analysis revealed increased structural damage in the glomerular and tubulointerstitial compartments within Ackr2(-/-) kidneys. This correlated with excessive renal leukocyte infiltration of CD4(+) T cells and mononuclear phagocytes with increased numbers in the tubulointerstitium but not glomeruli in knockout mice. Expression of inflammatory mediators and especially markers of fibrotic tissue remodeling were increased along with higher levels of ACKR2 inflammatory chemokine ligands like CCL2 in nephritic Ackr2(-/-) kidneys. In vitro, Ackr2 deficiency in TNF-stimulated tubulointerstitial tissue but not glomeruli increased chemokine levels. These results are in line with ACKR2 expression in interstitial lymphatic endothelial cells, which also assures efflux of activated leukocytes into regional lymph nodes. Consistently, nephritic Ackr2(-/-) mice showed reduced adaptive cellular immune responses indicated by decreased regional T-cell activation. However, this did not prevent aggravated injury in the kidneys of Ackr2(-/-) mice with nephrotoxic nephritis due to simultaneously increased tubulointerstitial chemokine levels, leukocyte infiltration and fibrosis. Thus, ACKR2 is important in limiting renal inflammation and fibrotic remodeling in progressive nephrotoxic nephritis. Hence, ACKR2 may be a potential target for therapeutic interventions in immune complex glomerulonephritis.
    Type of Publication: Journal article published
    PubMed ID: 29395335
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  • 7
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; MICE ; ACTIVATION ; DNA ; INFECTION ; kidney ; MECHANISM ; murine ; SERA ; renal ; CONTRAST ; DENDRITIC CELLS ; mechanisms ; INJECTION ; antibodies ; PROGRESSION ; ESCHERICHIA-COLI ; EPITHELIAL-CELLS ; VIRAL-INFECTION ; AUTOIMMUNITY ; BACTERIAL CPG-DNA ; CHEMOKINE RECEPTOR ; chemokines,autoimmune diseases,kidney,lupus,immunity ; IMMUNE-COMPLEX GLOMERULONEPHRITIS ; IMMUNIZATION ; NZB/NZW MICE ; SYSTEMIC-LUPUS-ERYTHEMATOSUS
    Abstract: How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL1pr/1pr mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL1pr/1pr mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL1pr/1pr mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG(2a) isotype in MRL1pr/1pr mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis
    Type of Publication: Journal article published
    PubMed ID: 14734643
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  • 8
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; CELL ; Germany ; VOLUME ; TISSUE ; MICE ; INJURIES ; kidney ; MACROPHAGES ; MECHANISM ; REDUCTION ; renal ; CONTRAST ; INTERVENTION ; T cell ; T cells ; T-CELL ; T-CELLS ; FLOW ; fibroblasts ; TARGET ; LYMPHOCYTES ; WILD-TYPE ; RECRUITMENT ; leukocyte ; glomerulonephritis ; NEPHROPATHY ; FLOW-CYTOMETRY ; chemokine ; ANTAGONIST ; INJURY ; HOST-DEFENSE ; CHEMOKINE RECEPTOR ; fibrosis ; INFILTRATION ; fibroblast ; flow cytometry ; collagen ; CCR5 ; INTERSTITIAL FIBROSIS ; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA ; MICE LACKING ; OBSTRUCTION ; TRANSPLANT REJECTION
    Abstract: As chemokine receptor CCR1 and CCR5 expression on circulating leukocytes is thought to contribute to leukocyte recruitment during renal fibrosis, the authors examined the effects of unilateral ureteral obstruction (UUO) in mice deficient for CCR1 or CCR5. Analysis of UUO kidneys from CCR1-deficient mice revealed a reduction of interstitial macrophages and lymphocytes (35% and 55%, respectively) compared with wild-type controls. CCR1-deficient mice had reduced CCR5 mRNA levels in UUO kidneys, which correlated with a reduction of CCR5+ T cell infiltrate as determined by flow cytometry. Interstitial fibroblasts, renal TGF-beta1 mRNA expression, interstitial volume, and collagen I deposits were all significantly reduced in CCR1-deficient mice. In contrast, renal leukocytes and fibrosis were unaffected in CCR5-deficient mice with UUO. However, if treated with the CCR1 antagonist BX471, CCR5-deficient mice showed a similar reduction of renal leukocytes and fibrosis as CCR1-deficient mice. To determine the underlying mechanism labeled macrophages and T cells isolated from either wild-type, CCR1-deficient, or CCR5-deficient mice were injected into wild-type mice with UUO. Three hours later, renal cell recruitment was reduced for CCR1-deficient cells or cells pretreated with BX471 compared with CCR5-deficient or wild-type cells. Thus, CCR1 but not CCR5 is required for leukocyte recruitment and fibrosis after UUO in mice. Therefore, CCR1 is a promising target for therapeutic intervention in leukocyte-mediated fibrotic tissue injury, e.g. progressive renal fibrosis
    Type of Publication: Journal article published
    PubMed ID: 14747380
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