Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps

Morshed, M.; Yousefi, Shída; Stöckle, Christina; Simon, Hans‐Uwe; Simon, Dagmar

doi:10.1111/j.1398-9995.2012.02868.x

Cited by 124 publications

(137 citation statements)

References 44 publications

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“…They have been recognized as effector cells in IgE-mediated allergic diseases (29), and in addition, there is increasing evidence that mast cells play a role in innate immune defense (30). For instance, mast cells were able to kill opsonized bacteria upon binding to complement or IgG Fc receptors, and endocytosis was observed via both oxidative and nonoxidative pathways (30).…”

Section: Mast Cell Extracellular Trapsmentioning

confidence: 99%

“…Recently, it has been reported that thymic stromal lymphopoietin (TSLP) and Staphylococcus aureus serve as strong stimuli for EET generation in the context of eosinophil adhesion (29). Like NETs, EETs and their ability to kill bacteria could be destroyed by deoxyribonuclease (DNase) (2).…”

Section: Eosinophil Extracellular Trapsmentioning

confidence: 99%

“…Evidence that mitochondrial and not nuclear DNA is released by eosinophils was obtained from live-cell imaging analyses showing that the DNA was derived from extranuclear cell structures, as well as from several molecular biological techniques (2). The DNA release took place in viable eosinophils in a catapult-like manner in less than 1 s. Neither in tissue nor in isolated blood eosinophils was EET production seen in association with eosinophil cell death, suggesting that the release of mitochondrial DNA and granule proteins is an active process by viable cells (2,29).…”

Section: Eosinophil Extracellular Trapsmentioning

confidence: 99%

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Extracellular DNA traps in allergic, infectious, and autoimmune diseases

Simon

Yousefi

2013

Allergy

Self Cite

102

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Extracellular DNA traps are part of the innate immune response and are seen with many infectious, allergic, and autoimmune diseases. They can be generated by several different leukocytes, including neutrophils, eosinophils, and monocytes, as well as mast cells. Here, we review the composition of these extracellular DNA-containing structures as well as potential mechanisms for their production and function. In general, extracellular DNA traps have been described as binding to and killing pathogens, particularly bacteria, fungi, but also parasites. On the other hand, it is possible that DNA traps contribute to immunopathology in chronic inflammatory diseases, such as bronchial asthma. In addition, it has been demonstrated that they can initiate and/or potentiate autoimmune diseases. Extracellular DNA traps represent a frequently observed phenomenon in inflammatory diseases, and they appear to participate in the cross-talk between different immune cells. These new insights into the pathogenesis of inflammatory diseases may open new avenues for targeted therapies.The formation of extracellular DNA traps has been reported as an efficient mechanism in host defense used by neutrophils (1), eosinophils (2), mast cells (3), and monocytes (4). These cells of the innate immune system play important roles in fighting against infections, particularly at barrier sites, where the organism comes in contact with the environment. Extracellular DNA traps have been shown to be able to bind and to kill bacteria (1-4) and fungi (5-7) in the extracellular space, but may also contribute to immunopathology (1, 2) or even cause autoimmunity (8-10). It should be noted that extracellular DNA-containing structures have also been described in plants, protecting the root tips against infections (11). The observations in plants support the concept that DNA, besides its function in maintaining and providing genetic information, can play an additional role in the innate immune system that is conserved from the plants via insects, various vertebrates to man (Fig. 1) (reviewed in 12).This article summarizes recent findings regarding the molecular composition of extracellular DNA traps, discusses some controversial issues regarding the origin of DNA fibers and the requirements for their release, and reviews the observations on these structures in diseased tissues and organs. We focus mainly on data obtained in human and mouse systems. We will first discuss the different cell types and the molecular mechanisms leading to extracellular DNA trap

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Section: Mast Cell Extracellular Trapsmentioning

confidence: 99%

Section: Eosinophil Extracellular Trapsmentioning

confidence: 99%

Section: Eosinophil Extracellular Trapsmentioning

confidence: 99%

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Extracellular DNA traps in allergic, infectious, and autoimmune diseases

Simon

Yousefi

2013

Allergy

Self Cite

102

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“…To block ROS generation, the NADPH oxidase inhibitor DPI (5 mM, except in concentration-dependence experiments) and the flavoprotein inhibitor MitoQ (1 mM) were added to basophils 10 min prior to stimulation. ROS generation was measured at different time points using a SpectraMax M2 plate reader (Bucher Biotec, Zurich, Switzerland) at 488 nM excitation and 530 nM emission for DHR and 510 nM excitation and 580 nM emission for MitoSOX Red (17,18).…”

Section: Reactive Oxygen Species Measurementsmentioning

confidence: 99%

NADPH Oxidase–Independent Formation of Extracellular DNA Traps by Basophils

Morshed

Hlushchuk

Simon

et al. 2014

The Journal of Immunology

143

120

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Basophils are primarily associated with a proinflammatory and immunoregulatory role in allergic diseases and parasitic infections. Recent studies have shown that basophils can also bind various bacteria both in the presence and the absence of opsonizing Abs. In this report, we show that both human and mouse basophils are able to produce mitochondrial reactive oxygen species and to form extracellular DNA traps upon IL-3 priming and subsequent activation of the complement factor 5 a receptor or FcεRI. Such basophil extracellular traps (BETs) contain mitochondrial, but not nuclear DNA, as well as the granule proteins basogranulin and mouse mast cell protease 8. BET formation occurs despite the absence of any functional NADPH oxidase in basophils. BETs can be found in both human and mouse inflamed tissues, suggesting that they also play a role under in vivo inflammatory conditions. Taken together, these findings suggest that basophils exert direct innate immune effector functions in the extracellular space.

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“…The bacterial killing assay was performed as previously described. 68 Briefly, primary bone marrow-derived neutrophils from WT and Atg5 NΔ mice (1 × 10 7 /ml) were resuspended in 200 μl of RPMI-1640 medium, supplemented with 2% FCS. In all, 20 μl of normal mouse sera was added to the neutrophils, followed by the addition of 220 μl of the opsonized bacteria.…”

Section: Ly6gmentioning

confidence: 99%

The generation of neutrophils in the bone marrow is controlled by autophagy

et al. 2014

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Autophagy has been demonstrated to have an essential function in several cellular hematopoietic differentiation processes, for example, the differentiation of reticulocytes. To investigate the role of autophagy in neutrophil granulopoiesis, we studied neutrophils lacking autophagy-related (Atg) 5, a gene encoding a protein essential for autophagosome formation. Using Cre-recombinase mediated gene deletion, Atg5-deficient neutrophils showed no evidence of abnormalities in morphology, granule protein content, apoptosis regulation, migration, or effector functions. In such mice, however, we observed an increased proliferation rate in the neutrophil precursor cells of the bone marrow as well as an accelerated process of neutrophil differentiation, resulting in an accumulation of mature neutrophils in the bone marrow, blood, spleen, and lymph nodes. To directly study the role of autophagy in neutrophils, we employed an in vitro model of differentiating neutrophils that allowed modulating the levels of ATG5 expression, or, alternatively, intervening pharmacologically with autophagy-regulating drugs. We could show that autophagic activity correlated inversely with the rate of neutrophil differentiation. Moreover, pharmacological inhibition of p38 MAPK or mTORC1 induced autophagy in neutrophilic precursor cells and blocked their differentiation, suggesting that autophagy is negatively controlled by the p38 MAPK-mTORC1 signaling pathway. On the other hand, we obtained no evidence for an involvement of the PI3K-AKT or ERK1/2 signaling pathways in the regulation of neutrophil differentiation. Taken together, these findings show that, in contrast to erythropoiesis, autophagy is not essential for neutrophil granulopoiesis, having instead a negative impact on the generation of neutrophils. Thus, autophagy and differentiation exhibit a reciprocal regulation by the p38-mTORC1 axis. Autophagy is an evolutionarily conserved mechanism, by which portions of cytoplasm are engulfed in a doublemembrane structure, known as the autophagosome, and delivered to lysosomes for subsequent degradation. Autophagy is dependent on autophagy-related (ATG) proteins. 1Autophagosome formation, elongation, and completion of enclosure require two ubiquitin-like conjugation systems: the first one generates the ATG5-ATG12 conjugate, which functions as a complex together with ATG16, and binds to the sequestering (pre-autophagosomal) phagophore. The second system conjugates an ATG8 homolog, LC3-I, with phosphatidylethanolamine to generate the lipidated LC3-II that associates with autophagosomes.2-4 The conversion of LC3-I into LC3-II represents a hallmark of autophagic activity and is widely used for the detection of autophagosome formation. Another frequently used marker for monitoring autophagic activity is p62, a protein, which is specifically degraded through autophagy. 5The vital role of autophagy in cell growth, development, and homeostasis has long been appreciated. Recent data also indicate its involvement in the differentiation of hematopoietic c...

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Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps

Abstract: thymic stromal lymphopoietin directly stimulates eosinophils to produce EETs. Our observations link epithelial TSLP expression triggered by environmental factors with pathogen defense mechanisms involving eosinophils.

Cited by 124 publications

References 44 publications

Extracellular DNA traps in allergic, infectious, and autoimmune diseases

Extracellular DNA traps in allergic, infectious, and autoimmune diseases

NADPH Oxidase–Independent Formation of Extracellular DNA Traps by Basophils

The generation of neutrophils in the bone marrow is controlled by autophagy

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