DNA binding to human leukocytes. Evidence for a receptor-mediated association, internalization, and degradation of DNA.

Bennett, Robert M.; Gábor, G; Merritt, Marcie

doi:10.1172/jci112226

Cited by 233 publications

(102 citation statements)

References 32 publications

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“…Previous studies performed by Bennett et al 35 supported the presence of a DNA-binding receptor on neutrophil plasma membrane which would be responsible for the endocytosis and degradation of exogenous DNA. Contrasting with our findings, they found that binding of l-phage DNA to neutrophils was dependent upon the presence of calcium and magnesium as well as sulfates.…”

Section: Discussionmentioning

confidence: 90%

Characterization of bacterial DNA binding to human neutrophil surface

Bass

Gabelloni

Álvarez

et al. 2008

Laboratory Investigation

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Bacterial DNA activates neutrophils through a CpG-and TLR9-independent mechanism. Neutrophil activation does not require DNA internalization, suggesting that it results from the interaction of bacterial DNA with a neutrophil surface receptor. The aim of this study was to characterize the interaction of bacterial DNA with the neutrophil surface. Bacterial DNA binding showed saturation and was inhibited by unlabeled DNA but not by other polyanions like yeast tRNA and poly-A. Resembling the conditions under which bacterial DNA triggers neutrophil activation, binding was not modified in the presence or absence of calcium, magnesium or serum. Treatment of neutrophils with proteases not only dramatically reduced bacterial DNA binding but also inhibited neutrophil activation induced by bacterial DNA. Experiments performed with DNA samples of different lengths obtained after digestion of bacterial DNA with DNase showed that only DNA fragments greater than E170-180 nucleotides competed bacterial DNA binding and retained the ability to trigger cell activation. Treatment of neutrophils with chemoattractants or conventional agonists significantly increased bacterial DNA binding. Moreover, neutrophils that underwent transmigration through human endothelial cell monolayers even in the absence of chemoattractants, exhibited higher binding levels of bacterial DNA. Together, our findings provide evidence that binding of bacterial DNA to neutrophils is a receptor-mediated process that conditions the ability of DNA to trigger cell activation. We speculate that neutrophil recognition of bacterial DNA might be modulated by the balance of agonists present at inflammatory foci. This effect might be relevant in bacterial infections with a biofilm etiology, in which extracellular DNA could function as a potent neutrophil agonist.

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Section: Discussionmentioning

confidence: 90%

Characterization of bacterial DNA binding to human neutrophil surface

Bass

Gabelloni

Álvarez

et al. 2008

Laboratory Investigation

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“…These findings have attracted much attention to the potential use of elevated concentration of cirDNA as a tumour marker. It is known that nucleic acids can bind with cell-surface DNA-binding proteins (Bennett et al, 1985;Laktionov et al, 1999), as well as with phospholipids of cellular membrane through bivalent ions (Beliaev et al, 1988). These interactions together with large amount of cells in the bloodstream provide an opportunity for circulation of DNA in blood being absorbed at cell surface.…”

Section: Discussionmentioning

confidence: 99%

Cell-free and cell-bound circulating DNA in breast tumours: DNA quantification and analysis of tumour-related gene methylation

et al. 2006

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Tumour development is characterised by the increased circulating DNA (cirDNA) concentration and by tumour-related changes in blood plasma DNA. Concentration of cirDNA and methylation of RARb2, RASSF1A and HIC-1 gene promoters were investigated in cell-free and cell-surface-bound fractions from healthy donors, patients with breast cancer, and patients with breast fibroadenoma. Tumour development was shown to lead to significant changes in the distribution of cirDNA between cell-free and cell-surfacebound fractions. Analysis of RARb2 and RASSF1A methylation in the total cirDNA provides 95% diagnostic coverage in breast cancer patients, 60% in patients with benign lesions, and is without false-positive results in healthy women. Results of the study indicate that methylation-specific PCR of RARb2 and RASSF1A genes based on the total cirDNA combined with the quantitative analysis of cirDNA distribution between cell-bound and cell-free fractions in blood provide the sensitive and accurate detection and discrimination of malignant and benign breast tumours.

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“…Several membrane proteins have been shown to play a role in binding and uptake of natural and synthetic DNA, but with the exception of Mac-1 and Scavenger Receptor A (SRA), putative oligonucleotide binding proteins have not been characterized either structurally or functionally [36,[41][42][43][44][45][46]. Benimetskaya et al [31] demonstrated that Mac-1 can bind oligonucleotides, but its role as a protein involved in binding of high molecular weight DNA has not yet been addressed.…”

Section: Discussionmentioning

confidence: 99%

Bacterial DNA activates human neutrophils by a CpG‐independent pathway

et al. 2003

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Bacterial DNA stimulates macrophages, monocytes, B lymphocytes, NK cells, and dendritic cells in a CpG-dependent manner. In this work we demonstrate that bacterial DNA, but not mammalian DNA, induces human neutrophil activation as assessed by L-selectin shedding, CD11b upregulation, and stimulation of cellular shape change, IL-8 secretion, and cell migration. Induction of these responses is not dependent on the presence of unmethylated CpG motifs, as neutrophil stimulatory properties were neither modified by CpG-methylation of bacterial DNA nor reproduced by oligonucleotides bearing CpG motifs. We found that human neutrophils express Toll-like receptor (TLR) 9 mRNA. However, as expected for a CpG-independent mechanism, activation does not involve a TLR9-dependent signaling pathway; neutrophil stimulation was not prevented by immobilization of bacterial DNA or by wortmannin or chloroquine, two agents that inhibit TLR9 signaling. Of note, both singlestranded and double-stranded DNA were able to induce activation, suggesting that neutrophils might be activated by bacterial DNA at inflammatory foci even in the absence of conditions required to induce DNA denaturation. Our findings provide the first evidence that neutrophils might be alerted to the presence of invading bacteria through recognition of its DNA via a novel mechanism not involving CpG motifs.

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DNA binding to human leukocytes. Evidence for a receptor-mediated association, internalization, and degradation of DNA.

Abstract: Previous studies have indicated that white blood cells possess DNA on their outer membranes. In this study we

Cited by 233 publications

References 32 publications

Characterization of bacterial DNA binding to human neutrophil surface

Characterization of bacterial DNA binding to human neutrophil surface

Cell-free and cell-bound circulating DNA in breast tumours: DNA quantification and analysis of tumour-related gene methylation

Bacterial DNA activates human neutrophils by a CpG‐independent pathway

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