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

Kitti Pazmandi, Zsofia Agod, Brahma V. Kumar, Attila Szabo, Tunde Fekete, Viktoria Sogor, Agota Veres, Istvan Boldogh, Eva Rajnavolgyi, Arpad Lanyi, Attila Bacsi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Inflammation is associated with oxidative stress and characterized by elevated levels of damage-associated molecular pattern (DAMP) molecules released from injured or even living cells into the surrounding microenvironment. One of these endogenous danger signals is the extracellular mitochondrial DNA (mtDNA) containing evolutionary conserved unmethylated CpG repeats. Increased levels of reactive oxygen species (ROS) generated by recruited inflammatory cells modify mtDNA oxidatively, resulting primarily in accumulation of 8-oxo-7,8-dihydroguanine (8-oxoG) lesions. In this study, we examined the impact of native and oxidatively modified mtDNAs on the phenotypic and functional properties of plasmacytoid dendritic cells (pDCs), which possess a fundamental role in the regulation of inflammation and T cell immunity. Treatment of human primary pDCs with native mtDNA up-regulated the expression of a costimulatory molecule (CD86), a specific maturation marker (CD83), and a main antigen-presenting molecule (HLA-DQ) on the cell surface, as well as increased TNF-α 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)-α 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-α 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.

Original languageEnglish (US)
Pages (from-to)281-290
Number of pages10
JournalFree Radical Biology and Medicine
Volume77
DOIs
StatePublished - Dec 1 2014

Fingerprint

Mitochondrial DNA
Dendritic Cells
Oxidative stress
Interferons
Molecules
Oxidative Stress
Toll-Like Receptor 9
Inflammation
HLA-DQ Antigens
T-cells
Interleukin-8
Immunity
Reactive Oxygen Species
Cells
T-Lymphocytes
Antigens
Peptides

Keywords

  • 8-Oxoguanine base
  • Extracellular mitochondrial DNA
  • Inflammation
  • Oxidative stress
  • Plasmacytoid dendritic cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. / Pazmandi, Kitti; Agod, Zsofia; Kumar, Brahma V.; Szabo, Attila; Fekete, Tunde; Sogor, Viktoria; Veres, Agota; Boldogh, Istvan; Rajnavolgyi, Eva; Lanyi, Arpad; Bacsi, Attila.

In: Free Radical Biology and Medicine, Vol. 77, 01.12.2014, p. 281-290.

Research output: Contribution to journalArticle

Pazmandi, Kitti ; Agod, Zsofia ; Kumar, Brahma V. ; Szabo, Attila ; Fekete, Tunde ; Sogor, Viktoria ; Veres, Agota ; Boldogh, Istvan ; Rajnavolgyi, Eva ; Lanyi, Arpad ; Bacsi, Attila. / Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. In: Free Radical Biology and Medicine. 2014 ; Vol. 77. pp. 281-290.
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AU - Fekete, Tunde

AU - Sogor, Viktoria

AU - Veres, Agota

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AU - Bacsi, Attila

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AB - Inflammation is associated with oxidative stress and characterized by elevated levels of damage-associated molecular pattern (DAMP) molecules released from injured or even living cells into the surrounding microenvironment. One of these endogenous danger signals is the extracellular mitochondrial DNA (mtDNA) containing evolutionary conserved unmethylated CpG repeats. Increased levels of reactive oxygen species (ROS) generated by recruited inflammatory cells modify mtDNA oxidatively, resulting primarily in accumulation of 8-oxo-7,8-dihydroguanine (8-oxoG) lesions. In this study, we examined the impact of native and oxidatively modified mtDNAs on the phenotypic and functional properties of plasmacytoid dendritic cells (pDCs), which possess a fundamental role in the regulation of inflammation and T cell immunity. Treatment of human primary pDCs with native mtDNA up-regulated the expression of a costimulatory molecule (CD86), a specific maturation marker (CD83), and a main antigen-presenting molecule (HLA-DQ) on the cell surface, as well as increased TNF-α 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)-α 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-α 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.

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