ORCID Profile
0000-0003-3646-8222
Current Organisations
Trinity College Dublin
,
University of Dublin Trinity College
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Publisher: Springer Science and Business Media LLC
Date: 16-02-2015
DOI: 10.1038/NM.3806
Publisher: Wiley
Date: 10-2017
Publisher: Wiley
Date: 09-2012
Abstract: The inflammatory cytokine IL-17 plays a critical role in immunity to infection and is involved in the inflammatory pathology associated with certain autoimmune diseases, such as psoriasis and rheumatoid arthritis. While CD4(+) and CD8(+) T cells are important sources of this cytokine, recent evidence has suggested that γδ T cells and a number of families of innate lymphoid cells (ILCs) can secrete IL-17 and related cytokines. The production of IL-17 by γδ T cells appears to be largely independent of T-cell receptor activation and is promoted through cytokine signalling, in particular by IL-23 in combination with IL-1β or IL-18. Therefore IL-17-secreting γδ T cells can be categorised as a family of cells similar to innate-like lymphoid cells. IL-17-secreting γδ T cells function as a part of mucosal defence against infection, with most studies to date focusing on their response to bacterial pathogens. γδ T cells also play a pathological role in certain autoimmune diseases, where they provide an early source of IL-17 and IL-21, which initiate responses mediated by conventional IL-17-secreting CD4(+) T cells (Th17 cells). ILCs lack an antigen receptor or other lineage markers, and ILC subsets that express the transcriptional factor RORγt have been found to secrete IL-17. Evidence is emerging that these newly recognised sources of IL-17 play both pathological and protective roles in inflammatory diseases as discussed in this article.
Publisher: Wiley
Date: 09-1998
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1016/J.BBI.2020.01.012
Abstract: Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, β-galactosidase and p16
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NI.1935
Publisher: EMBO
Date: 02-07-2010
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1038/MI.2014.93
Publisher: Wiley
Date: 15-01-2013
DOI: 10.1038/ICB.2012.82
Abstract: Autophagy is a cellular mechanism for the sequestration and degradation of intracellular pathogens and compromised organelles, particularly damaged mitochondria. Autophagy also clears other cellular components, such as inflammasomes and cytokines, thus providing an important means of regulating inflammation. Defects in autophagy have been found by genetic association studies to confer susceptibility to several autoimmune and inflammatory disorders, particularly inflammatory bowel disease. Thus, the manipulation of autophagy in disease situations is of growing interest for therapeutic targeting however, the involvement of autophagy in cellular homoeostasis, in normal immune function and in inflammation is manifold. An appreciation of the intricacies of the contributions of this process to inflammation, and how these are altered by various immune and environmental stimuli, is essential for the understanding and interpretation of studies of inflammation and the design of therapeutics exploiting the manipulation of autophagy. This review focuses on the known roles of autophagy in the induction and maintenance of inflammation and on its role in the aetiology and regulation of inflammatory and autoimmune disorders.
Publisher: Rockefeller University Press
Date: 20-05-2013
DOI: 10.1084/JEM.20121588
Abstract: Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22–responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti–IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CELREP.2019.08.072
Abstract: The NLRP3 inflammasome is a cytosolic complex sensing phagocytosed material and various damage-associated molecular patterns, triggering production of the pro-inflammatory cytokines interleukin-1 beta (IL)-1β and IL-18 and promoting pyroptosis. Here, we characterize glutathione transferase omega 1-1 (GSTO1-1), a constitutive deglutathionylating enzyme, as a regulator of the NLRP3 inflammasome. Using a small molecule inhibitor of GSTO1-1 termed C1-27, endogenous GSTO1-1 knockdown, and GSTO1-1
Publisher: Elsevier BV
Date: 11-2000
DOI: 10.1016/S0165-5728(00)00366-0
Abstract: Neurological side effects are a major cause of concern following immunization with a number of vaccines, especially the whole cell pertussis vaccine (Pw). In this study we report that IL-1beta concentrations were significantly increased in the hippoc us following subcutaneous (s.c.) injection of Pw, and that this was accompanied by increased activity of the stress-activated kinase, c-Jun-N-terminal kinase (JNK) and a decrease in glutamate release. These effects were mimicked by s.c injection of active pertussis toxin (PT) or lipopolysaccharide (LPS). Incubation of hippoc al synaptosomes in the presence of Pw, PT or LPS also resulted in increased JNK activation and decreased glutamate release, effects which were mimicked by IL-1beta and blocked by the IL-1 receptor antagonist (IL-ra). Our observations are consistent with the hypothesis that IL-1beta induced by active bacterial toxins present in vaccine preparations, mediate the neurochemical and perhaps the neurological effects of Pw.
Publisher: The American Association of Immunologists
Date: 15-10-2012
Abstract: Autophagy controls IL-1β secretion by regulating inflammasome activation and by targeting pro–IL-1β for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling it was abrogated with an IL-1R antagonist or with IL-1–neutralizing Abs, whereas treatment with either rIL-1α or IL-1β induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted enhanced levels of both IL-1β and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-γ, and IL-22 by γδ T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1999
DOI: 10.1097/00001756-199906230-00004
Abstract: It is widely accepted that interleukin-1beta (IL-1beta), a cytokine produced not only by cells of the immune system but also by cells of the central nervous system, modulates hippoc al function. Here we investigate the effect of a seizure-induced increase in hippoc al IL-1beta concentration on neurotransmitter release. We report that oral administration of glycerol evoked seizure activity in BALB/c mice. Associated with these convulsions was an induction of IL-1beta gene expression and a significant increase in cytokine protein in the hippoc us. Release of glutamate in synaptosomes prepared from hippoc i of these animals was reduced compared to control. These results are consistent with previous data suggesting a modulatory effect of IL-1beta on glutamate release in hippoc us.
Publisher: Elsevier BV
Date: 2000
DOI: 10.1016/S0165-5728(99)00177-0
Abstract: Parenteral injection of endotoxin has been used as a model to examine the role of pro-inflammatory cytokines in the centrally controlled responses to Gram-negative bacterial infection. However, the events that occur following mucosal exposure to live bacteria have received little attention. In this study, we have used a murine model to demonstrate that respiratory infection with Bordetella pertussis, which is associated with a number of systemic complications including fever, seizure and encephalopathy in children, resulted in persistent expression of mRNA transcripts for IL-1beta and TNFalpha and transient expression of IL-6 in the hippoc us and hypothalamus. These changes correlated with elevated levels of cytokine protein in the same brain areas. The results demonstrate that infection at a mucosal surface can result in the induction of pro-inflammatory cytokine production in the brain and suggest that these locally synthesized mediators may contribute to the centrally controlled clinical manifestations of B. pertussis infection.
Publisher: Oxford University Press (OUP)
Date: 04-2013
DOI: 10.1189/JLB.1012543
Abstract: Review of the activation of inflammasome processes IL-1β and IL-18, which synergize with IL-23 to promote IL-17 production, by IL-17-secreting γδ T and Th17 cells. NLRs are members of the PRR family that sense microbial pathogens and mediate host innate immune responses to infection. Certain NLRs can assemble into a multiprotein complex called the inflammasome, which activates casapse-1 required for the cleavage of immature forms of IL-1β and IL-18 into active, mature cytokines. The inflammasome is activated by conserved, exogenous molecules from microbes and nonmicrobial molecules, such as asbestos, alum, or silica, as well as by endogenous danger signals, such as ATP, amyloid-β, and sodium urate crystals. Activation of the inflammasome is a critical event triggering IL-1-driven inflammation and is central to the pathology of autoinflammatory diseases, such as gout and MWS. Recent studies have also shown IL-1 or IL-18, in synergy with IL-23, can promote IL-17-prduction from Th17 cells and γδ T cells, and this process can be regulated by autophagy. IL-1-driven IL-17 production plays a critical role in host protective immunity to infection with fungi, bacteria, and certain viruses. However, Th17 cells and IL-17-seceting γδ T cells, activated by inflammasome-derived IL-1 or IL-18, have major pathogenic roles in many autoimmune diseases. Consequently, inflammasomes are now major drug targets for many autoimmune and chronic inflammatory diseases, as well as autoinflammatory diseases.
Publisher: American Physiological Society
Date: 10-2013
DOI: 10.1152/AJPENDO.00297.2013
Abstract: Emerging evidence has demonstrated that saturated fatty acids prime pro-IL-1β production and inflammasome-mediated IL-1β activation is critical in obesity-associated insulin resistance (IR). Nonetheless, IL-1 receptor I-deficient (IL-1RI −/− ) mice develop mature-onset obesity despite consuming a low-fat diet (LFD). With this apparent contradiction, the present study evaluated whether IL-1RI −/− mice were protected against long-term (6 mo) high-fat diet (HFD)-induced IR. Male wild-type and IL-1RI −/− mice were fed LFD or HFD for 3 or 6 mo, and glucose and insulin tolerance tests were performed. Adipose insulin sensitivity, cytokine profiles, and adipocyte morphology were assessed. The adipogenic potential of stromal vascular fraction was determined. Hepatic lipid accumulation and insulin sensitivity were characterized. IL-1RI −/− mice developed glucose intolerance and IR after 6 mo HFD compared with 3 mo HFD, coincident with enhanced weight gain, hyperinsulinemia, and hyperleptinemia. The aggravated IR phenotype was associated with loss of adipose functionality, switch from adipocyte hyperplasia to hypertrophy and hepatosteatosis. Induction of adipogenic genes was reduced in IL-1RI −/− preadipocytes after 6 mo HFD compared with 3 mo HFD. Obese LFD-IL-1RI −/− mice exhibited preserved metabolic health. IL-1RI −/− mice develop glucose intolerance and IR after 6 mo HFD intervention. While mature-onset obesity is evident in LFD-IL-1RI −/− mice, the additional metabolic insult of HFD was required to drive adipose inflammation and systemic IR. These findings indicate an important interaction between dietary fat and IL-1, relevant to optimal metabolic health.
Publisher: Informa UK Limited
Date: 10-05-2016
Publisher: Elsevier BV
Date: 09-2012
Publisher: Wiley
Date: 10-2019
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring ex les of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.
Publisher: American Society for Microbiology
Date: 07-2001
DOI: 10.1128/IAI.69.7.4217-4223.2001
Abstract: Immunization with the whole-cell pertussis vaccine (Pw), while effective at preventing whooping cough in infants, has been associated with local, systemic, and neuronal reactions, including fevers and convulsions in children. In contrast, the new acellular pertussis vaccines (Pa) have a considerably improved safety profile. The lack of an appropriate animal model has restricted investigations into the mechanisms by which neurological reactions are induced by vaccination. Here we describe a novel murine model wherein seizure-like behavioral changes are induced following parenteral administration of Pw. The proinflammatory cytokine interleukin-β (IL-1β), production of which has been associated with many neurodegenerative conditions, was significantly increased in the hippoc us and hypothalamus of vaccinated animals. Accompanying this change was a decrease in release of the inhibitory neurotransmitters γ-aminobutyric acid and adenosine in the hippoc us. Seizure-like behavioral changes were significantly reduced following inhibition of IL-1β production by the administration of an inhibitor of IL-1β-converting enzyme and were almost completely abrogated in IL-1 receptor type I knockout mice. These results suggest a causal relationship between IL-1β induction and convulsive behavior following Pw vaccination. Significantly, Pa neither increased IL-1β nor induced behavioral changes in mice, but did induce the anti-inflammatory cytokine IL-10. In contrast, administration of active pertussis toxin and lipopolysaccharide, residual in Pw but absent from Pa, also induced convulsive activity. Our findings provide the first direct evidence of an immunological basis for pertussis vaccine reactogenicity and suggest that active bacterial toxins are responsible for the neurologic disturbances observed in children immunized with Pw.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2023
DOI: 10.1038/S41467-023-39174-1
Abstract: Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF gene name F3 ) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli , and S. aureus , with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2012
DOI: 10.1038/NI.2450
Abstract: A June 2012 meeting in Dublin, Ireland, showcased advances in the understanding of the role of IL-17 and related cytokines in host immunity and how these cytokines have been successfully targeted for the treatment of autoimmunity.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kingston Mills.