Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Lande, Roberto; Gregorio, Josh; Facchinetti, Valeria; Chatterjee, Bithi; Wang, Yi Hong; Homey, Bernhard; Cao, Wei; Wang, Yui Hsi; Su, Bing; Nestle, Frank O.; Żal, Tomasz; Mellman, Ira; Schröder, Jens-Michael; Liu, Yong Jun; Gilliet, Michel

doi:10.1038/nature06116

Cited by 1,571 publications

(1,676 citation statements)

References 43 publications

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“…Besides its antimicrobial properties, LL-37 contributes to the uptake of extracellular DNA by various cell types binding the DNA by virtue of its opposite charges. As previously reported, LL-37 can convert inert self nuclear DNA into a potent inducer of IFN-Į production from pDCs by protecting extracellular DNA from degradation and forming aggregated and condensed complexes with DNA that are delivered to and retained within early endocytic compartments to trigger TLR9 [26]. Furthermore, binding of LL-37 to CpG-rich bacterial DNA significantly reduces the time required for pDCs and B cells to sense the presence of bacterial DNA via TLR [48].…”

Section: Discussionmentioning

confidence: 58%

“…4). Previous studies have reported that nuclear DNA alone is not able to trigger the production of IFN-Į by human pDCs, while nuclear DNA pre-incubated with human cathelicidin (LL-37), an antimicrobial peptide, is capable of doing so [26]. Based on this previous finding, mtDNA samples were pre-incubated with LL-37 before addition to the cell cultures.…”

Section: Neither Native Nor Oxidatively Modified Mtdna Alone Is Able mentioning

confidence: 98%

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Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Pázmándi

Agod

Kumar

et al. 2014

Free Radical Biology and Medicine

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Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed. 2014.09.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.www.elsevier.com/locate/freeradbiomed Abbreviations: 7-AAD, 7-aminoactinomycin-D; 8-oxoG, 8-oxo-7,8-dihydroguanine; 8-oxodG, 8-oxo-7,8-dihydro-2'- well as increased TNF-Į and IL-8 production from the cells. These effects were more apparent when pDCs were exposed to oxidatively modified mtDNA. Neither native nor oxidized mtDNA molecules were able to induce interferon (IFN)-Į secretion from pDCs unless they formed a complex with human cathelicidin LL-37, an antimicrobial peptide.Interestingly, simultaneous administration of a Toll-like receptor (TLR)9 antagonist abrogated the effects of both native and oxidized mtDNAs on human pDCs. In a murine model, oxidized mtDNA also proved a more potent activator of pDCs compared to the native form, except for induction of IFN-Į production. Collectively, we demonstrate here for the first time that elevated levels of 8-oxoG bases in the extracellular mtDNA induced by oxidative stress increase the immunostimulatory capacity of mtDNA on pDCs. 3 HighlightsWe compared the immunostimulatory capacity of native and oxidized mtDNA on pDCs.8-Oxoguanin-containing mtDNA has a greater capacity to activate primary human pDCs.In vivo, oxidized mtDNA also proved a more potent activator of pDC than native mtDNA.

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Section: Discussionmentioning

confidence: 58%

Section: Neither Native Nor Oxidatively Modified Mtdna Alone Is Able mentioning

confidence: 98%

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Pázmándi

Agod

Kumar

et al. 2014

Free Radical Biology and Medicine

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“…In psoriasis, a recently reported mechanism of PDCs activation is based on the production of the endogenous antimicrobial peptide LL37 by damaged keratinocytes. LL37 is able to bind and convert self-DNA or self-RNA into potent TLR-dependent PDCs triggers [64,65]. Remarkably, LL37 is induced strongly in the lesional epidermis of psoriasis biopsies [66].…”

Section: Box 1 the Chemerin/chemr23 Axis In Inflammationmentioning

confidence: 99%

Trafficking properties of plasmacytoid dendritic cells in health and disease

Sozzani

Vermi

Prete

et al. 2010

Trends in Immunology

138

147

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“…The activation of DCs by NETs appears to play an important role in the pathogenesis of some autoimmune diseases such as psoriasis (Lande et al, 2007), systemic lupus erythematosus (SLE) (Barrat et al, 2005;Garcia-Romo et al, 2011;Lande et al, 2011;Means et al, 2005) small vessel vasculitis (Sangaletti et al, 2012) and type I diabetes (Diana et al, 2013). NETsactivated pDCs produce large amounts of interferon that can lead to the maturation of myeloid DCs (mDCs) and exert an effect on T cell function.…”

mentioning

confidence: 99%

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Tillack

Naegele

Haueis

et al. 2013

Journal of Neuroimmunology

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Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis. Abstract (100 words)Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis.Key words: Neutrophil, neutrophil extracellular traps (NETs), multiple sclerosis, genderCirculating NETs in MS patients 3 1-IntroductionThe main function of the innate immune system during infection is to eliminate the pathogen, and neutrophils are key players in innate immune responses.Women of reproductive age are more resistant to sepsis and subsequent morbidity and mortality than men (Schroder et al., 1998), and the incidence of sepsis in postmenopausal women increases to levels almost equal to those seen in age-matched men (Martin et al., 2003). Women also have a higher systemic neutrophil count compared with men (Bain and England, 1975a), and neutrophil counts correlate with estradiol levels during menstruation (Bain and England, 1975b) and pregnancy (Efrati et al., 1964) suggesting that sex hormones influence neutrophilia and overall resistance to sepsis most likely by delaying apoptosis in neutrophils (Molloy et al., 2003). In order to eliminate pathogens during infections, neutrophils are armed with a variety of weapons including engulfment and intracellular degradation of microbes (Hampton et al., 1998;Segal, 2005), release of oxygen species and granule proteins (Lehrer and Ganz, 1999) and release of extracellular chromatin fibers bound to granular, nuclear and cytoplasmic proteins called neutrophil extracellular traps (NETs) (Brinkmann et al., 2004). NETs not only trap and kill pathogens very efficiently but also minimize collateral tissue damage by containing proteases to the DNA fibers and act as physical barriers preventing microbial spread. Despite the well documented importance of NETs as an effective antimicrobial first line defense mechanism, there is increasing ...

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Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

Cited by 1,571 publications

References 43 publications

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Trafficking properties of plasmacytoid dendritic cells in health and disease

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

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