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Article ; Online: The role of neutrophil extracellular traps in rheumatic diseases.

Apel, Falko / Zychlinsky, Arturo / Kenny, Elaine F

2018 Volume 14, Issue 8, Page(s) 467–475

Abstract: Rheumatic diseases are a collection of disorders defined by the presence of inflammation and destruction of joints and internal organs. A common feature of these diseases is the presence of autoantibodies targeting molecules commonly expressed in ... ...

Abstract	Rheumatic diseases are a collection of disorders defined by the presence of inflammation and destruction of joints and internal organs. A common feature of these diseases is the presence of autoantibodies targeting molecules commonly expressed in neutrophils. These preformed mediators are released by neutrophils but not by other immune cells such as macrophages. Neutrophils, major players in the host innate immune response, initiate a cell death mechanism termed neutrophil extracellular trap (NET) formation as a way to ensnare pathogens. NETs are also a source of released self-molecules found in rheumatic diseases. Subsequently, research on the role of NETs in the onset, progression and resolution of inflammation in rheumatic diseases has intensified. This Review has two aims. First, it aims to highlight the mechanisms required for the generation of NETs, the research landscape of which is rapidly changing. Second, it aims to discuss the role of neutrophils and NETs in systemic lupus erythematosus, vasculitis (specifically anti-neutrophil cytoplasmic autoantibody-associated vasculitis), rheumatoid arthritis and gout. Our goal is to clarify the field of NET research in rheumatic diseases in the hope of improving the therapeutic approaches utilized for these diseases.
MeSH term(s)	Animals ; Anti-Infective Agents/pharmacology ; Anti-Infective Agents/therapeutic use ; Disease Progression ; Extracellular Traps/drug effects ; Extracellular Traps/metabolism ; Humans ; Immunity, Innate/drug effects ; Neutrophils/immunology ; Rheumatic Diseases/drug therapy ; Rheumatic Diseases/immunology
Chemical Substances	Anti-Infective Agents
Language	English
Publishing date	2018-06-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2491532-4
ISSN	1759-4804 ; 1759-4790
ISSN (online)	1759-4804
ISSN	1759-4790
DOI	10.1038/s41584-018-0039-z
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Article ; Online: Dnase1-deficient mice spontaneously develop a systemic lupus erythematosus-like disease.

Kenny, Elaine F / Raupach, Bärbel / Abu Abed, Ulrike / Brinkmann, Volker / Zychlinsky, Arturo

European journal of immunology

2019 Volume 49, Issue 4, Page(s) 590–599

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi-organ damage. SLE is characterized by dysregulated activation of T- and B-lymphocytes and the production of autoantibodies directed against ... ...

Abstract	Systemic lupus erythematosus (SLE) is an autoimmune disease that has high morbidity and can result in multi-organ damage. SLE is characterized by dysregulated activation of T- and B-lymphocytes and the production of autoantibodies directed against nuclear components. The endonuclease deoxyribonuclease 1 (DNase1) is abundant in blood and a subset of SLE patients have mutations in DNASE1. Furthermore, a report showed that Dnase1-deficient mice develop an SLE-like disease, but these mice also carry a deletion of the gene adjacent to Dnase1, which encodes the chaperone TRAP1/HSP75. We generated a murine strain deficient in Dnase1 with an intact Trap1 gene to examine if a lack of DNase1 is responsible for the development of a spontaneous SLE-like disease. We show that the Dnase1-deficient mice do indeed develop an SLE-like phenotype with elevated autoantibody production by 9 months and kidney damage by 12 months. Notably, this model recapitulates the female bias seen in human SLE patients since female Dnase1-deficient mice produced the highest concentrations of autoantibodies and had more severe kidney damage than males. Since there is currently no cure for SLE the protective role of DNase1 as demonstrated in our study remains of great therapeutic interest.
MeSH term(s)	Animals ; Autoantibodies/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Biomarkers ; Biopsy ; Deoxyribonuclease I/deficiency ; Disease Models, Animal ; Female ; Genetic Association Studies/methods ; Genetic Predisposition to Disease ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Lupus Erythematosus, Systemic/etiology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/pathology ; Lupus Nephritis/etiology ; Lupus Nephritis/metabolism ; Lupus Nephritis/pathology ; Male ; Mice ; Mice, Knockout ; Sex Factors
Chemical Substances	Autoantibodies ; Biomarkers ; HSP90 Heat-Shock Proteins ; Deoxyribonuclease I (EC 3.1.21.1)
Language	English
Publishing date	2019-02-21
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201847875
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Article ; Online: Diverse stimuli engage different neutrophil extracellular trap pathways.

Kenny, Elaine F / Herzig, Alf / Krüger, Renate / Muth, Aaron / Mondal, Santanu / Thompson, Paul R / Brinkmann, Volker / Bernuth, Horst von / Zychlinsky, Arturo

eLife

2017 Volume 6

Abstract: Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, ...

Abstract	Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin,
Language	English
Publishing date	2017-06-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.24437
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Article ; Online: The balancing act of neutrophils.

Bardoel, Bart W / Kenny, Elaine F / Sollberger, Gabriel / Zychlinsky, Arturo

Cell host & microbe

2014 Volume 15, Issue 5, Page(s) 526–536

Abstract: Neutrophils are endowed with a plethora of toxic molecules that are mobilized in immune responses. These cells evolved to fight infections, but when deployed at the wrong time and in the wrong place, they cause damage to the host. Here, we review the ... ...

Abstract	Neutrophils are endowed with a plethora of toxic molecules that are mobilized in immune responses. These cells evolved to fight infections, but when deployed at the wrong time and in the wrong place, they cause damage to the host. Here, we review the generalities of these cells as well as the difficulties encountered when trying to unravel them mechanistically. We then focus on how neutrophils develop and their function in infection. We center our attention on human neutrophils and what we learn from clinical immunodeficiencies. Finally, we use autoimmune disease to illustrate the harmful potential of dysregulated neutrophil responses.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Humans ; Infections/immunology ; Neutrophils/immunology
Language	English
Publishing date	2014-05-16
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2014.04.011
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Article ; Online: Increased Salt Intake for Orthostatic Intolerance Syndromes: A Systematic Review and Meta-Analysis.

Loughlin, Elaine A / Judge, Conor S / Gorey, Sarah E / Costello, Maria M / Murphy, Robert P / Waters, Ruairi F / Hughes, Diarmaid S / Kenny, Rose Ann / O'Donnell, Martin J / Canavan, Michelle D

The American journal of medicine

2020 Volume 133, Issue 12, Page(s) 1471–1478.e4

Abstract: Background: Guidelines recommend increased salt intake as a first-line recommendation in the management of symptomatic orthostatic hypotension and recurrent syncope. There have been no systematic reviews of this intervention. We sought to summarize the ... ...

Abstract	Background: Guidelines recommend increased salt intake as a first-line recommendation in the management of symptomatic orthostatic hypotension and recurrent syncope. There have been no systematic reviews of this intervention. We sought to summarize the evidence for increased salt intake in patients with orthostatic intolerance syndromes. Methods: We conducted a systematic review and meta-analysis of studies in PubMed, EMBASE, and CINAHL. Interventional studies that increased salt intake in individuals with orthostatic intolerance syndromes were included. Primary outcome measures included incidence of falls and injuries, and rates of syncope and presyncope. Secondary outcome measures included other orthostatic intolerance symptoms, blood pressure, and heart rate. Results: A total of 14 studies were eligible, including participants with orthostatic hypotension, syncope, postural orthostatic tachycardia syndrome, and idiopathic orthostatic tachycardia (n = 391). Mean age was 35.6 (± 15) years. All studies were small and short-term (<60 mins-90 days). No study reported on the effect of increased salt intake on falls or injuries. Meta-analysis demonstrated that during head-up tilt, mean time to presyncope with salt intake increased by 1.57 minutes (95% confidence interval [CI], 1.26-1.88), mean systolic blood pressure increased by 12.27 mm Hg (95% CI, 10.86-13.68), and mean heart rate decreased by -3.97 beats per minute (95% CI, -4.08 to -3.86), compared with control. Increased salt increased supine blood pressure by 1.03 mm Hg (95% CI, 0.81 to 1.25). Increased salt intake resulted in an improvement or resolution of symptoms in 62.3% (95% CI, 51.6 to 72.6) of participants in short-term follow-up studies (mean follow-up of 44.3 days, 6 studies; n=91). Methodological quality of studies were low with high statistical heterogeneity in all meta-analyses. Conclusions: Our meta-analysis provides low-quality evidence of a short-term improvement in orthostatic intolerance with increased salt intake. There were no clinical trials demonstrating the efficacy and safety of increased salt intake on long-term clinical outcomes. Overall, there is a paucity of clinical trial evidence to support a cornerstone recommendation in the management of orthostatic intolerance syndromes.
MeSH term(s)	Adult ; Humans ; Middle Aged ; Orthostatic Intolerance/diet therapy ; Sodium Chloride, Dietary/administration & dosage ; Young Adult
Chemical Substances	Sodium Chloride, Dietary
Language	English
Publishing date	2020-06-27
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2020.05.028
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Article ; Online: Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment.

Kenny, Aidan / McArdle, Hazel / Calero, Miguel / Rabano, Alberto / Madden, Stephen F / Adamson, Kellie / Forster, Robert / Spain, Elaine / Prehn, Jochen H M / Henshall, David C / Medina, Miguel / Jimenez-Mateos, Eva M / Engel, Tobias

Biomolecules

2019 Volume 9, Issue 11

Abstract: The need for practical biomarkers for early diagnosis of Alzheimer's disease (AD) remains largely unmet. Here we investigated the use of blood-based microRNAs as prognostic biomarkers for AD and their application in a novel electrochemical microfluidic ... ...

Abstract	The need for practical biomarkers for early diagnosis of Alzheimer's disease (AD) remains largely unmet. Here we investigated the use of blood-based microRNAs as prognostic biomarkers for AD and their application in a novel electrochemical microfluidic device for microRNA detection. MicroRNA transcriptome was profiled in plasma from patients with mild cognitive impairment (MCI) and AD. MicroRNAs Let-7b and microRNA-206 were validated at elevated levels in MCI and AD, respectively. MicroRNA-206 displayed a strong correlation with cognitive decline and memory deficits. Longitudinal follow-ups over five years identified microRNA-206 increases preceding the onset of dementia. MicroRNA-206 was increased in unprocessed plasma of AD and MCI subjects, detected by our microfluidic device. While increased Let-7b levels in plasma may be used to identify patients with MCI, changes in plasma levels of microRNA-206 may be used to predict cognitive decline and progression towards dementia at an MCI stage. MicroRNA quantification via a microfluidic device could provide a practical cost-effective tool for the stratification of patients with MCI according to risk of developing AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/blood ; Alzheimer Disease/etiology ; Cognitive Dysfunction/blood ; Cognitive Dysfunction/complications ; Female ; Humans ; Male ; MicroRNAs/blood
Chemical Substances	MIRN206 microRNA, human ; MicroRNAs ; mirnlet7 microRNA, human
Language	English
Publishing date	2019-11-13
Publishing country	Switzerland
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom9110734
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Article ; Online: Signalling adaptors used by Toll-like receptors: an update.

Kenny, Elaine F / O'Neill, Luke A J

Cytokine

2008 Volume 43, Issue 3, Page(s) 342–349

Abstract: Research into the five Toll/IL1 receptor (TIR) adaptor proteins involved in innate immunity continues to advance. Here we outline some of the more recent findings. MyD88 has a key role in signalling by the IL1 receptor complex and TLRs. However, a MyD88- ... ...

Abstract	Research into the five Toll/IL1 receptor (TIR) adaptor proteins involved in innate immunity continues to advance. Here we outline some of the more recent findings. MyD88 has a key role in signalling by the IL1 receptor complex and TLRs. However, a MyD88-independent pathway of IL1beta signalling in neurons has been described which involves the protein kinase Akt, and which has an anti-apoptotic effect. This pathway may also be important for the mechanism whereby Alum exerts its adjuvant effect since this depends on IL1beta but is MyD88-independent. MyD88 is also involved in tumourigenesis in models of hepatocarcinoma and familial associated polyposis (FAP); negative regulation of TLR3 signalling and in PKCepsilon activation. The adaptor Mal is regulated by phosphorylation and caspase-1 cleavage. A variant form of Mal in humans termed S180L confers protection in multiple infectious diseases. TRAM is controlled by myristoylation and phosphorylation and the localisation of TRAM with TLR4 to endosomes is required for activation of IRF3 and induction of IFNbeta. Finally SARM has been shown to regulate TRIF and also appears to be involved in neuronal injury mediated by oxidative stress in mouse neurons. These advances confirm the importance for the TIR domain-containing adapters in host defence and inflammation.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Adaptor Proteins, Vesicular Transport/physiology ; Animals ; Armadillo Domain Proteins/physiology ; Caspase 1/metabolism ; Cytoskeletal Proteins/physiology ; Endosomes/physiology ; Humans ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/physiology ; Mice ; Myeloid Differentiation Factor 88/physiology ; Protein Kinase C-epsilon/physiology ; Receptors, Interleukin-1/genetics ; Receptors, Interleukin-1/physiology ; Toll-Like Receptor 3/physiology ; Toll-Like Receptor 4/physiology ; Toll-Like Receptors/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Armadillo Domain Proteins ; Cytoskeletal Proteins ; Membrane Glycoproteins ; Myeloid Differentiation Factor 88 ; Receptors, Interleukin-1 ; SARM1 protein, human ; TICAM-1 protein, mouse ; TICAM2 protein, human ; TIRAP protein, human ; TLR4 protein, human ; Toll-Like Receptor 3 ; Toll-Like Receptor 4 ; Toll-Like Receptors ; Protein Kinase C-epsilon (EC 2.7.11.13) ; Caspase 1 (EC 3.4.22.36)
Language	English
Publishing date	2008-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2008.07.010
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Article ; Online: Itm2a silencing rescues lamin A mediated inhibition of 3T3-L1 adipocyte differentiation.

Davies, Stephanie J / Ryan, James / O'Connor, Patrick B F / Kenny, Elaine / Morris, Derek / Baranov, Pavel V / O'Connor, Rosemary / McCarthy, Tommie V

Adipocyte

2017 Volume 6, Issue 4, Page(s) 259–276

Abstract: Dysregulation of adipose tissue metabolism is associated with multiple metabolic disorders. One such disease, known as Dunnigan-type familial partial lipodystrophy (FPLD2) is characterized by defective fat metabolism and storage. FPLD2 is caused by a ... ...

Abstract	Dysregulation of adipose tissue metabolism is associated with multiple metabolic disorders. One such disease, known as Dunnigan-type familial partial lipodystrophy (FPLD2) is characterized by defective fat metabolism and storage. FPLD2 is caused by a specific subset of mutations in the LMNA gene. The mechanisms by which LMNA mutations lead to the adipose specific FPLD2 phenotype have yet to be determined in detail. We used RNA-Seq analysis to assess the effects of wild-type (WT) and mutant (R482W) lamin A on the expression profile of differentiating 3T3-L1 mouse preadipocytes and identified Itm2a as a gene that was upregulated at 36 h post differentiation induction in these cells. In this study we identify Itm2a as a novel modulator of adipogenesis and show that endogenous Itm2a expression is transiently downregulated during induction of 3T3-L1 differentiation. Itm2a overexpression was seen to moderately inhibit differentiation of 3T3-L1 preadipocytes while shRNA mediated knockdown of Itm2a significantly enhanced 3T3-L1 differentiation. Investigation of PPARγ levels indicate that this enhanced adipogenesis is mediated through the stabilization of the PPARγ protein at specific time points during differentiation. Finally, we demonstrate that Itm2a knockdown is sufficient to rescue the inhibitory effects of lamin A WT and R482W mutant overexpression on 3T3-L1 differentiation. This suggests that targeting of Itm2a or its related pathways, including autophagy, may have potential as a therapy for FPLD2.
MeSH term(s)	3T3-L1 Cells ; Adipocytes/cytology ; Adipocytes/metabolism ; Adipogenesis ; Animals ; Cell Differentiation/genetics ; Fibroblasts/metabolism ; Gene Expression ; Gene Knockdown Techniques ; Gene Silencing ; Genes, Reporter ; Lamin Type A/genetics ; Lipodystrophy, Familial Partial/genetics ; Lipodystrophy, Familial Partial/pathology ; Membrane Proteins/genetics ; Mice ; Promoter Regions, Genetic
Chemical Substances	Itm2a protein, mouse ; Lamin Type A ; Membrane Proteins
Language	English
Publishing date	2017-09-05
Publishing country	United States
Document type	Journal Article
ISSN	2162-397X
ISSN (online)	2162-397X
DOI	10.1080/21623945.2017.1362510
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Article ; Online: Diverse stimuli engage different neutrophil extracellular trap pathways

Elaine F Kenny / Alf Herzig / Renate Krüger / Aaron Muth / Santanu Mondal / Paul R Thompson / Volker Brinkmann / Horst von Bernuth / Arturo Zychlinsky

eLife, Vol

2017 Volume 6

Abstract	Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA-induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a related pathway for NET induction, whereas ionophores require an alternative pathway but that NETs produced by all stimuli are proteolytically active, kill bacteria and composed mainly of chromosomal DNA. Thus, we demonstrate that NETosis occurs through several signalling mechanisms, suggesting that extrusion of NETs is important in host defence.
Keywords	Neutrophil ; Neutrophil Extracellular Traps ; NETs ; reactive oxygen species ; cell death ; signal transduction ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-06-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article ; Online: Bruton's tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin.

Kenny, Elaine F / Quinn, Susan R / Doyle, Sarah L / Vink, Paul M / van Eenennaam, Hans / O'Neill, Luke A J

PloS one

2013 Volume 8, Issue 8, Page(s) e74103

Abstract: B cells signal through both the B cell receptor (BCR) which binds antigens and Toll-like receptors (TLRs) including TLR9 which recognises CpG DNA. Activation of TLR9 synergises with BCR signalling when the BCR and TLR9 co-localise within an auto- ... ...

Abstract	B cells signal through both the B cell receptor (BCR) which binds antigens and Toll-like receptors (TLRs) including TLR9 which recognises CpG DNA. Activation of TLR9 synergises with BCR signalling when the BCR and TLR9 co-localise within an auto-phagosome-like compartment. Here we report that Bruton's tyrosine kinase (BTK) is required for synergistic IL6 production and up-regulation of surface expression of MHC-class-II, CD69 and CD86 in primary murine and human B cells. We show that BTK is essential for co-localisation of the BCR and TLR9 within a potential auto-phagosome-like compartment in the Namalwa human B cell line. Downstream of BTK we find that calcium acting via calmodulin is required for this process. These data provide new insights into the role of BTK, an important target for autoimmune diseases, in B cell activation.
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase ; Animals ; Autoimmunity ; Calcium/metabolism ; Calmodulin/metabolism ; Cell Line ; Humans ; Inositol 1,4,5-Trisphosphate/metabolism ; Interleukin-6/biosynthesis ; Mice ; Mice, Inbred C57BL ; Phagosomes/metabolism ; Phospholipase C gamma/metabolism ; Protein Transport ; Protein-Tyrosine Kinases/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction ; Toll-Like Receptor 9/metabolism
Chemical Substances	Calmodulin ; Interleukin-6 ; Receptors, Antigen, B-Cell ; Toll-Like Receptor 9 ; Inositol 1,4,5-Trisphosphate (85166-31-0) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; BTK protein, human (EC 2.7.10.2) ; Btk protein, mouse (EC 2.7.10.2) ; Phospholipase C gamma (EC 3.1.4.3) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2013-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0074103
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