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Efficient Renal Recruitment of Macrophages and T Cells in Mice Lacking the Duffy Antigen/Receptor for Chemokines

Medizinische Poliklinik, Campus Innenstadt, Ludwig-Maximilians-University Munich, Munich, Germany.
American Journal Of Pathology (Impact Factor: 4.6). 08/2009; 175(1):119-31. DOI: 10.2353/ajpath.2009.080590
Source: PubMed

ABSTRACT The Duffy antigen/receptor for chemokines (DARC) is a chemokine-binding protein that is expressed on erythrocytes and renal endothelial cells. DARC-mediated endothelial transcytosis of chemokines may facilitate the renal recruitment of macrophages and T cells, as has been suggested for neutrophils. We studied the role of Darc in two mouse models of prolonged renal inflammation, one that primarily involves the tubulointerstitium (unilateral ureteral obstruction), and one that requires an adaptive immune response that leads to glomerulonephritis (accelerated nephrotoxic nephritis). Renal expression of Darc and its ligands was increased in both models. Leukocytes effectively infiltrated obstructed kidneys in Darc-deficient mice with pronounced T-cell infiltration at early time points. Development of interstitial fibrosis was comparable in both genotypes. Nephrotoxic nephritis was inducible in Darc-deficient mice, with both an increased humoral immune response and functional impairment during the early phase of disease. Leukocytes efficiently infiltrated kidneys of Darc-deficient mice, with increased cell numbers at early but not late time points. Taken together, renal inflammation developed more rapidly in DARC-deficient mice, without affecting the extent of renal injury at later time points. Thus, genetic elimination of Darc in mice does not prevent the development of renal infiltrates and may even enhance such development during the early phases of interstitial and glomerular diseases in mouse models of prolonged renal inflammation.

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    • "Most of the previous studies on Darc regulation of inflammation were based upon LPS challenges, chemokine injections or chronic diseases [37], [47], [48], [49]. Dawson et al., [47] reported that there was no difference between the WT and Darc-KO mice in LPS-induced leukocyte recruitment to the peritoneal cavity which was the injection site at two hours post-LPS injection, but they noticed more leukocytes accumulation in the lung and liver in the KO mice compared to WT mice. Lee et al., [37] have found that mice that lack Darc in erythrocytes showed reduced neutrophils in lung airspaces compared to WT control mice 4 hours after intratracheal instillation of LPS. "
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    ABSTRACT: There is now considerable experimental data to suggest that inflammatory cells collaborate in the healing of skeletal fractures. In terms of mechanisms that contribute to the recruitment of inflammatory cells to the fracture site, chemokines and their receptors have received considerable attention. Our previous findings have shown that Duffy antigen receptor for chemokines (Darc), the non-classical chemokine receptor that does not signal, but rather acts as a scavenger of chemokines that regulate cell migration, is a negative regulator of peak bone density in mice. Furthermore, because Darc is expressed by inflammatory and endothelial cells, we hypothesized that disruption of Darc action will affect post-fracture inflammation and consequently will affect fracture healing. To test this hypothesis, we evaluated fracture healing in mice with targeted disruption of Darc and corresponding wild type (WT) control mice. We found that fracture callus cartilage formation was significantly greater (33%) at 7 days post-surgery in Darc-KO compared to WT mice. The increased cartilage was associated with greater Collagen (Col) II expression at 3 days post-fracture and Col-X at 7 days post-fracture compared to WT mice, suggesting that Darc deficiency led to early fracture cartilage formation and differentiation. We then compared the expression of cytokine and chemokine genes known to be induced during inflammation. Interleukin (Il)-1β, Il-6, and monocyte chemotactic protein 1 were all down regulated in the fractures derived from Darc-KO mice at one day post-fracture, consistent with an altered inflammatory response. Furthermore, the number of macrophages was significantly reduced around the fractures in Darc-KO compared to WT mice. Based on these data, we concluded that Darc plays a role in modulating the early inflammatory response to bone fracture and subsequent cartilage formation. However, the early cartilage formation was not translated with an early bone formation at the fracture site in Darc-KO compared to WT mice.
    PLoS ONE 10/2013; 8(10):e77362. DOI:10.1371/journal.pone.0077362 · 3.23 Impact Factor
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    • "and interstitial fibrosis, however, with minimal glomerular lesions. Thus inflammatory cells are thought to play an important role in post-UUO pathology (Vielhauer et al., 2009), together with several factors affecting the progression of tubulo interstitial fibrosis (Guerrot et al., 2011; Lian et al., 2011; Nasu et al., 2012; Omori et al., 2012). Adenosine A 2A receptor (A 2A R) is reported to be involved in tissue repair and inflammation, such as the development of skin fibrosis, liver fibrosis and autoimmune nephritis (Chan et al., 2006; Fernandez et al., 2008; Garcia et al., 2011). "
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    ABSTRACT: Adenosine A(2A) receptor (A(2A)R) plays an important regulatory role in the processes of inflammation and fibrosis. However, it is unknown whether A(2A)R can mediate renal interstitial fibrosis (RIF). To evaluate the effect of genetic A(2A)R knockout (KO) on the pathological progress of RIF, we applied a unilateral ureteral obstruction (UUO) model of RIF on A(2A)R KO mice and their wild-type (WT) littermates. Renal pathological assessment was performed at different post-UUO stages using hematoxylin and eosin (H&E) and Masson's trichrome staining as well as quantitative morphological analysis. Our data demonstrated that: (i) the extent of RIF was determined by the development of UUO in a time-dependent manner; (ii) A(2A)R KO exacerbated the pathological progress of RIF in mice at the early post-UUO stage, i.e. day 3 and day 7; (iii) the profibrotic effect of A(2A)R KO was prominent until the late post-UUO stage, i.e. day 14, at which RIF reached a similar severity level in A(2A)R KO and WT mice. Our findings revealed that A(2A)R KO significantly exacerbated the progression of UUO-induced RIF in mice, prominently at the initial stage.
    Acta histochemica 09/2012; 115(4). DOI:10.1016/j.acthis.2012.09.002 · 1.76 Impact Factor
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    • "Furthermore, chemokine presentation on renal endothelial cells was absent, and renal neutrophil recruitment was impaired, in the context of lower inflammatory chemokine levels during systemic inflammation (Zarbock et al., 2007). In contrast, Vielhauer et al. (2009) studied tubule-interstitial inflammation and glomerulonephritis in DARC-deficient mice and demonstrated that in these models macrophage and T lymphocytes were recruited equally well in DARC KO and wild type mice. Both human and murine studies suggest that DARC can sustain inflammatory chemokines levels on erythrocytes and in plasma (Jilma-Stohlawetz et al., 2001; Fukuma et al., 2003), but the biological purpose of this reservoir function is not clear. "
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    Frontiers in Immunology 08/2012; 3:266. DOI:10.3389/fimmu.2012.00266
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