Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Abstract: OBJECTIVE: Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21-a member of cyclin-dependent kinase inhibitors-can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP. DESIGN: We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))-a model to study AIP development-with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. RESULTS: p21 deficiency in LT mice (LTp21(-/-)) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T-B cell infiltration. Interestingly, LT and LTp21(-/-) mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-kappaB pathway activation remained impaired in LTp21(-/-) pancreata. CONCLUSIONS: Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 28774888
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; Germany ; IN-VIVO ; VITRO ; DISEASE ; EXPOSURE ; RNA ; TISSUE ; MICE ; ACTIVATION ; DNA ; INFECTION ; kidney ; MECHANISM ; AUTOIMMUNE-DISEASE ; CONTRAST ; DENDRITIC CELLS ; mechanisms ; T-CELLS ; cytokines ; ACID ; AGE ; INTERFERON ; INFECTIONS ; DOUBLE-STRANDED-RNA ; INTERFERON-ALPHA ; PERIPHERAL-BLOOD ; chemokine ; AUTOANTIBODIES ; SERUM ; AUTOIMMUNITY ; SINGLE ; interaction ; MONOCYTE CHEMOATTRACTANT PROTEIN-1 ; dendritic cell ; INNATE ANTIVIRAL RESPONSES ; MRL-FAS(LPR) MICE ; PLASMACYTOID DENDRITIC CELLS
    Abstract: How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL1pr/1pr mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL1pr/1pr mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN-alpha levels. A course of 50 mu g of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL1pr/1pr mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL1pr/1pr mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis
    Type of Publication: Journal article published
    PubMed ID: 15772251
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: ACID, AMINO-ACID, AMINO-ACID-RESIDUES, ASSAY, basement membrane, BASEMENT-MEMBRANE, BASIC RESIDUES,
    Abstract: T cells are differentially recruited to the tubulointerstitium during renal inflammation. The selective presentation of chemokines by surface structures may in part underlie this phenomenon. In an attempt to better characterize the presentation of chemokines by tissue environments an exemplary chemokine with a well-defined structure was selected, and a binding assay for the protein on fixed archival tissue sections was developed. This article describes the selective binding of the chemokine CCL5 to renal structures. CCL5 was shown to bind to endothelial regions, interstitial extracellular matrix, tubular epithelial cells, and tubular basement membranes but rarely to glomerular structures in well-preserved kidneys. In contrast, binding of CCL5 to glomerular components was seen in renal biopsies with acute allograft glomerulitis (in which T cells accumulate in glomeruli). The N terminus mediates receptor binding, whereas two clusters of basic amino acid residues ((RKNR47)-R-44 and (KKVVVR59)-K-55) are involved in the presentation of CCL5 by extracellular structures. Mutation of either loop abrogated CCL5 binding to tissue sections. Variations of the N terminus and a mutation that prevents higher order oligomerization did not change the binding pattern. The data suggest that renal compartments differ in their capacity to present chemokines, which may help explain the differential recruitment of leukocytes during allograft injury. Both clusters of basic residues in CCL5 are necessary for sufficient binding of CCL5 to tissue sections
    Type of Publication: Journal article published
    PubMed ID: 17494888
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
  • 6
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; CELL ; Germany ; human ; DISEASE ; DISEASES ; POPULATION ; GENE-EXPRESSION ; TIME ; PATIENT ; INJURIES ; LIGAND ; MESANGIAL CELLS ; NEPHRITIS ; RESPONSES ; kidney ; MARKER ; renal ; T cell ; T cells ; T-CELL ; T-CELLS ; antibodies ; antibody ; FORM ; TARGET ; NO ; immunohistochemistry ; DIFFERENCE ; NUMBER ; MARKERS ; LYMPHOCYTES ; MIGRATION ; LIGANDS ; RECRUITMENT ; T-LYMPHOCYTES ; T lymphocyte ; TARGETS ; glomerulonephritis ; NEPHROPATHY ; RECEPTORS ; DIFFERENTIAL EXPRESSION ; chemokine ; T lymphocytes ; INJURY ; PROGNOSTIC MARKERS ; targeting ; CHEMOKINE RECEPTOR ; ABSENCE ; COMPARTMENTS ; PATTERN ; CCR5 ; TRANSPLANT REJECTION ; CD3 ; REAL-TIME ; mRNA ; GLOMERULAR-DISEASES ; RENAL BIOPSIES ; CHEMOKINE RECEPTORS ; CHEMOKINE RECEPTOR CXCR3 ; chemokines ; HUMAN KIDNEY-DISEASES ; INDUCIBLE PROTEIN-10 ; lupus ; LYMPHOCYTE-FIBROBLAST INTERACTIONS ; MESANGIAL CELL ; PROLIFERATIVE GLOMERULONEPHRITIS
    Abstract: Chemokines play pivotal roles in the recruitment of inflammatory cells into the kidney. The chemokine receptors CXCR3 and CCR5 are expressed on activated T lymphocytes, and expression of CXCR3 by mesangial cells has been suggested. Detailed description of CXCR3 expression might form a rational basis for use as a diagnostic marker and for therapeutic CXCR3 targeting in human glomerulonephritis. We studied the expression of CXCR3 in renal biopsies by immunohistochemistry (n = 45), and real time RTPCR (n = 78). Biopsies were from patients with IgA nephropathy, lupus nephritis, and membranoproliferative glomerulonephritis. Furthermore, cultured human mesangial cells (HMC) were studied for CXCR3 expression, and for functional responses to the ligands CXCL10/IP-10 and CXCL9/Mig. CXCR3-positive cells were rarely found in glomerular tufts, but formed a major part of the tubulointerstitial infiltrates. Consistently, CXCR3 mRNA expression was too low to be quantified in glomerular compartments, and was not detectable in HMC. The published staining for CXCR3 of mesangial cells could be traced to cross-reactivity of an antibody for CXCR3 with a potentially related chemokine receptor as revealed by FACS analysis. Despite an absence of CXCR3 expression, mesangial cells reacted to CXCR3 ligands by proliferation and migration, which was blocked by pertussis toxin but not by an anti-CXCR3 antibody. These results indicate that HMC do not express the classical CXCR3, but may potentially express a related receptor with shared ligand specificity. By immunohistochemistry the number of CXCR3-positive cells, mainly interstitial T cells, correlated with renal function, proteinuria, and percentage of globally sclerosed glomeruli. A significant morphological and numerical correlation between CD3, CXCR3, and CCR5-positive cells indicated a CXCR3/CCR5 double-positive T cell population. No apparent difference in the CXCR3 expression pattern was found between disease entities. CXCR3 expression was localized to interstitial T cells, and these cells correlated strongly with important prognostic markers. Therefore interstitial CXCR3, as well as CCR5-positive T cells might play an important role during progressive loss of renal function, and are potential therapeutic targets in human glomerular diseases
    Type of Publication: Journal article published
    PubMed ID: 14742268
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Abstract: The kidney is the most frequently transplanted solid organ. Recruitment of inflammatory cells, ranging from diffuse to nodular accumulations with defined microarchitecture, is a hallmark of acute and chronic renal allograft injury. Lymphotoxins (LTs) mediate the communication of lymphocytes and stromal cells and play a pivotal role in chronic inflammation and formation of lymphoid tissue. The aim of this study was to assess the expression of members of the LT system in acute rejection (AR) and chronic renal allograft injury such as transplant glomerulopathy (TG) and interstitial fibrosis/tubular atrophy (IFTA). We investigated differentially regulated components in transcriptomes of human renal allograft biopsies. By microarray analysis, we found the upregulation of LTbeta, LIGHT, HVEM and TNF receptors 1 and 2 in AR and IFTA in human renal allograft biopsies. In addition, there was clear evidence for the activation of the NFkappaB pathway, most likely a consequence of LTbeta receptor stimulation. In human renal allograft biopsies with transplant glomerulopathy (TG) two distinct transcriptional patterns of LT activation were revealed. By quantitative RT-PCR robust upregulation of LTalpha, LTbeta and LIGHT was shown in biopsies with borderline lesions and AR. Immunohistochemistry revealed expression of LTbeta in tubular epithelial cells and inflammatory infiltrates in transplant biopsies with AR and IFTA. Finally, activation of LT signaling was reproduced in a murine model of renal transplantation with AR. In summary, our results indicate a potential role of the LT system in acute renal allograft rejection and chronic transplant injury. Activation of the LT system in allograft rejection in rodents indicates a species independent mechanism. The functional role of the LT system in acute renal allograft rejection and chronic injury remains to be determined.
    Type of Publication: Journal article published
    PubMed ID: 29300739
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: albumin, ALBUMINURIA, AUTOANTIBODIES, AUTOIMMUNITY, CELL, CELLS, DNA, DOWN-REGULATION, endothelial c
    Abstract: P〉What are the molecular mechanisms of bacterial infections triggering or modulating lupus nephritis? In nephritic MRLlpr/lpr mice, transient exposure to bacterial cell wall components such as lipopeptide or lipopolysaccharide (LPS) increased splenomegaly, the production of DNA autoantibodies, and serum interleukin (IL)-6, IL-12 and tumour necrosis factor (TNF) levels, and aggravated lupus nephritis. Remarkably, bacterial lipopeptide induced massive albuminuria in nephritic but not in non-nephritic mice. This was associated with down-regulation of renal nephrin mRNA and redistribution from its normal localization at foot processes to the perinuclear podocyte area in nephritic MRLlpr/lpr mice. Bacterial lipopeptide activates Toll-like receptor 2 (TLR2), which we found to be expressed on cultured podocytes and glomerular endothelial cells. TNF and interferon (IFN)-gamma induced TLR2 mRNA and receptor expression in both cell types. Albumin permeability was significantly increased in cultured podocytes and glomerular endothelial cells upon stimulation by bacterial lipopeptide. LPS also induced moderate albuminuria. In summary, bacterial lipopeptide and LPS can aggravate glomerulonephritis but only lipopeptide potently induces severe albuminuria in MRLlpr/lpr mice
    Type of Publication: Journal article published
    PubMed ID: 19175801
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Keywords: BIOPSY, BONE, CELL, CELLS, DC-SIGN, dendritic cell, DENDRITIC CELLS, DISEASE, DISEASES, EXPRESSION,
    Abstract: Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases
    Type of Publication: Journal article published
    PubMed ID: 18368027
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...