Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense

Yousefi, Shída; Gold, Jeffrey A.; Andina, Nicola; Lee, James J.; Kelly, Ann Marie; Kozlowski, Evelyne; Schmid, Inès; Straumann, Alex; Reichenbach, Janine; Gleich, Gerald J.; Simon, Hans‐Uwe

doi:10.1038/nm.1855

Cited by 821 publications

(884 citation statements)

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“…These data indicate that extracellular mtDNA acting as a DAMP can contribute to innate immune responses. As mtDNA can be released from various cell types during infections or under inflammatory conditions closely associated with oxidative stress [32,33], in this work we examined the immunostimulatory properties of oxidatively damaged mtDNA on pDCs, which exert a crucial role in the regulation of inflammation and T cell immunity [34].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…69 Eosinophils demonstrate protective mechanisms that rely on degranulation in bacterial infections 70 and release mitochondrial DNA in a unique way that clumps bacteria together. 71 In addition, antiviral effects have been reported. 72 Investigations of the role of eosinophils in fungal infection with Candida albicans, [73][74][75] Alternaria alternata, 76 or C. neoformans 10,23,41,42 were made, with a focus on their effector function.…”

Section: Discussionmentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ⌬dblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ⌬dblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. Cryptococcus neoformans is a facultative intracellular pathogen that is acquired by inhalation of spores and/or desiccated yeasts and leads to latent pulmonary infection in immunocompetent humans. 1 The development of cryptococcal meningitis occurs mainly in immunocompromised HIV-1-infected patients, most likely by reactivation of latent pulmonary C. neoformans infection. 2 It is estimated that 504,000 HIV-1-infected patients die every year from cryptococcal meningitis in sub-Saharan Africa, 3 which surprisingly exceeds the annual death rate of tuberculosis-associated HIV cases. Resistance against C. neoformans primarily involves monocytic effector mechanisms. 4 -6 In this context, T helper (Th) cells are central regulatory players with profound effects. Whereas IL-12-dependent Th1 responses are protective, with an additional contribution by IL-23-dependent Th17 responses, 7-9 Th2 cells producing IL-4, IL-13, and IL-5 are detrimental. 10,11 Studies 12-14 that used i.v. inoculation examined the traversal of the blood-brain barrier by C. neoformans and led to the conclusion that transmigration can occur with intracellular and extracellular fungi. In case of bronchopulmonary infection, dissemination seems to rely more on Th2 cytokines. This allergic Th2-driven inflammation represents the immunopathological pathway promoting disease by allowing cryptococci to grow inside the lung and finally enabling dissemination to the brain, ultimately causing fatal meningoencephalitis. 15 This sequela is accompanied by development of IL-4/IL-13-dependent alternatively activated macrophages, suggesting that those cells may be involved in dissemination. Alternatively activated macrophages are found only in susceptible mice 15 and show significantly reduced control of intracellular growth. 5 In addition, IL-13-dependent mucus production by goblet cells, IL-4 -...

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“…In response to several stimuli, neutrophils and eosinophils can release the so-called neutrophil extracellular traps (NETs), that is, microbicidal structures composed of nuclear chromatin, histones and granular antimicrobial proteins. 157,158 Upon the administration of granulocytemacrophage colony-stimulating factor (GMCSF) or short-term stimulations with the complement fragment C5a, two rather physiological conditions, NETs are generated by viable cells, as demonstrated by several observations: (i) no cytosolic proteins are detected in NETs; (ii) NET-releasing cells fail to take up exclusion dyes; and (iii) NETs can be detected within 30-60 min after stimulation with IL-8 and lipopolysaccharide. 158,159 However, following non-physiological stimulation with phorbol-12-myristate-13-acetate, NETs are released by a subset of neutrophils undergoing a peculiar form of cell death, 160 which has been dubbed 'netosis'.…”

Section: Tentative Definition Of Other Cell Death Modalitiesmentioning

confidence: 99%

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

et al. 2011

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proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense

Cited by 821 publications

References 31 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

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

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