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  • 1
    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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  • 2
    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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