Li, L. et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J. Clin. Invest. 122, 3931-3942

The Journal of clinical investigation (Impact Factor: 13.22). 10/2012; 122(11). DOI: 10.1172/JCI63170
Source: PubMed


DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI.

Download full-text


Available from: Diane L Rosin, Aug 07, 2014
1 Follower
74 Reads
  • Source
    • "Depletion of macrophage [30] [34], neutrophils [35], CD4 T cells [31], B cells [33], or NKT cells (with NK1.1 mAb) [26] is protective against ischemia reperfusion injury of the kidney, whereas depletion of regulatory T cells (Treg) exacerbates AKI [36]. Recent studies suggest that the administration of Treg or adenosine treated dendritic cells before ischemia is also protective [36] [37]. In contrast to the above observations, opposing views on the role of adaptive immune systems in ischemia reperfusion injury have also been documented [38] [39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute kidney injury (AKI) is a common problem in the hospital setting and intensive care unit. Despite improved understanding, there are no effective therapies available to treat AKI. A large body of evidence strongly suggests that ischemia reperfusion injury is an inflammatory disease mediated by both adaptive and innate immune systems. Cell migration also plays an important role in embryonic development and inflammation, and this process is highly regulated to ensure tissue homeostasis. One such paradigm exists in the developing nervous system, where neuronal migration is mediated by a balance between chemoattractive and chemorepulsive signals. The ability of the guidance molecule netrin-1 to repulse or abolish attraction of neuronal cells expressing the UNC5B receptor makes it an attractive candidate for the regulation of inflammatory cell migration. Recent identification of netrin-1 as regulators of immune cell migration has led to a large number of studies looking into how netrin-1 controls inflammation and inflammatory cell migration. This review will focus on recent advances in understanding netrin-1 mediated regulation of inflammation during acute and chronic kidney disease and whether netrin-1 and its receptor activation can be used to treat acute and chronic kidney disease.
    Mediators of Inflammation 06/2014; 2014:525891. DOI:10.1155/2014/525891 · 3.24 Impact Factor
  • Source
    • "Activation of A2AR increases intracellular cAMP, which is a potent inhibitor of the NF-κB pathway downstream of immunoreceptors. Thus, A2AR may contribute to the anti-inflammatory effects of A2AR agonists [37]. Adenosine is an important anti-inflammatory molecule. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neutrophil gelatinase-associated lipocalin (NGAL) is emerging as a mediator of various biological and pathological states. However, the specific biological role of this molecule remains unclear, as it serves as a biomarker for many conditions. The high sensitivity of NGAL as a biomarker coupled with relatively low specificity may hide important biological roles. Data point toward an acute compensatory, protective role for NGAL in response to adverse cellular stresses, including inflammatory and oxidative stress. The aim of this study was to understand whether NGAL modulates the T-cell response through regulation of the human leukocyte antigen G (HLA-G) complex, which is a mediator of tolerance. Peripheral blood mononuclear cells (PBMCs) were obtained from eight healthy donors and isolated by centrifugation on a Ficoll gradient. All donors gave informed consent. PBMCs were treated with four different concentrations of NGAL (40-320 ng/ml) in an iron-loaded or iron-free form. Changes in cell phenotype were analyzed by flow cytometry. NGAL stimulated expression of HLA-G on CD4+ T cells in a dose- and iron-dependent manner. Iron deficiency prevented NGAL-mediated effects, such that HLA-G expression was unaltered. Furthermore, NGAL treatment affected stimulation of regulatory T cells and in vitro expansion of CD4(+) CD25(+) FoxP3(+) cells. An NGAL neutralizing antibody limited HLA-G expression and significantly decreased the percentage of CD4(+) CD25(+) FoxP3(+) cells. We provide in vitro evidence that NGAL is involved in cellular immunity. The potential role of NGAL as an immunomodulatory molecule is based on its ability to induce immune tolerance by upregulating HLA-G expression and expansion of T-regulatory cells in healthy donors. Future studies should further evaluate the role of NGAL in immunology and immunomodulation and its possible relationship to immunosuppressive therapy efficacy, tolerance induction in transplant patients, and other immunological disorders.
    PLoS ONE 02/2014; 9(2):e89497. DOI:10.1371/journal.pone.0089497 · 3.23 Impact Factor
  • Source
    • "As demonstrated in liver IRI, the CD4+ subset of NKT cells are activated rapidly after renal IRI, which is followed by the activation of other immune cells (68). Blocking dendritic cell mediated NKT cell activation via A2AR agonist treatment markedly reduced renal injury (69). Indeed, inhibition of adenosine receptor signaling is required for optimal dendritic cell, and subsequent T cell, activation (70). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracellular adenosine is a potent immunomodulatory molecule that accumulates in states of inflammation. Nucleotides such as adenosine triphosphate and adenosine diphosphate are release from injured and necrotic cells and hydrolyzed to adenosine monophosphate and adenosine by the concerted action of the ectonucleotidases CD39 and CD73. Accumulating evidence suggest that purinergic signaling is involved in the inflammatory response that accompanies acute rejection and chronic allograft dysfunction. Modification of the purinergic pathway has been shown to alter graft survival in a number of solid organ transplant models and the response to ischemia-reperfusion injury (IRI). Furthermore, the purinergic pathway is intrinsically involved in B and T cell biology and function. Although T cells have traditionally been considered the orchestrators of acute allograft rejection, a role for B cells in chronic allograft loss is being increasingly appreciated. This review focuses on the role of the ectonucleotidases CD39 and CD73 and adenosine signaling in solid organ transplantation including the effects on IRI and T and B cell biology.
    Frontiers in Immunology 02/2014; 5:64. DOI:10.3389/fimmu.2014.00064
Show more