199 results on '"O'Reilly, Steven"'
Search Results
152. IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics.
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O'Reilly, Steven, Ciechomska, Marzena, Fullard, Nicola, Przyborski, Stefan, and van Laar, Jacob M.
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- 2016
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153. Tumour necrosis factor α RECEPTOR activated T cells of patients with systemic sclerosis are deficient in IL-10 expression but promote myofibroblast differentiation via IL-6 and TGF-β.
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Hügle, Thomas, Krippner-Heidenreich, Anja, Simpson, Rachel, Kraaij, Marina, O'Reilly, Steven, Bigley, Venetia, Collin, Matthew, Iversen, Line, and van Laar, Jacob M
- Abstract
Background and objectives Systemic sclerosis (SSc) is an auto-inflammatory multisystem disease leading to fibrosis of the skin and inner organs. T lymphocytes are key effector cells in the affected tissue. The role of lymphocytes in the transition from inflammation to fibrosis is unclear. Previous data suggested a possible pro-fibrotic effect of tumour necrosis factor–receptor (TNF-R) 2. Materials and methods Skin punch biopsies from affected skin of 12 SSc patients (six limited, six diffuse) were digested in dispase and collagenase and processed for multicolour flow cytometry (CD45, HLA-DR, auto-fluorescence, CD14, CD1a, C3, CD4, CD8, TNF-R1 and 2). α-Smooth muscle actin (α-SMA) positive myofibroblasts and CD3 lymphocytes were furthermore quantified in skin biopsies of 26 patients of a control SSc patient cohort by immunohistochemistry. For functional analyses, T lymphocytes were isolated from peripheral blood of 12 patients using CD3 selection and activation via ± CD3/CD28 beads. TNF-R were stimulated with selective CysTNF mutants at concentrations of 100 ng/ml. Real-time PCR and multiplex cytokine assay was performed for cytokine expression. Fibroblasts of SSc patients were incubated in conditioned (TNF-R stimulated) lymphocyte medium; α-SMA was detected by Western blot. Results Higher numbers of lymphocytes per CD45 cells (45.7% vs 26.6%), but less CD1a (1.0% vs 4.1%) cells were detected in the dermis of patients with diffuse SSc compared to limited SSc. Lymphocyte infiltration correlated with skin thickening (modified Rodnan skin score, mRSS) of the patients (p=0.004) and myofibroblast infiltration (p<0.05). TNF-R2 was significantly up-regulated on CD3, CD4 and CD8 subsets in patients with diffuse but not limited disease. TNF-R1 was not significantly upregulated on dermal lymphocytes. The mean intensity fluorescence of TNF-R2 but not 1 correlated with the mRSS (p=0.01). Activation of SSc lymphocytes selective TNF-R agonists showed that TNF-R1 stimulation resulted in a significantly higher interleukin (IL)-6 expression whereas TNF-R2 stimulation lead to a higher TGF-β expression, compared to healthy individuals. Conversely, CD3/CD28 activated lymphocytes of SSc patients expressed significantly less IL-10 upon TNF-R2 stimulation compared to lymphocytes from healthy individuals. When the authors incubated control fibroblasts in conditioned medium, medium from healthy TNF-activated lymphocytes α-SMA expression. In contrast, conditioned medium from TNF-activated SSc lymphocytes α-SMA expression. In dermis of a SSc patient who underwent lymphoablative treatment, the authors observed a reduced number of myofibroblasts and lymphocytes with a reversibility of TNF-R2 expression. Conclusion Lymphocyte infiltration and TNF-R expression play a role in SSc via enhanced IL-6, TGF-β and myofibroblast differentiation. Deficient IL-10 expression might impair the resolution of inflammation in SSc. [ABSTRACT FROM PUBLISHER]
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- 2011
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154. The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 4-Octyl Itaconate, Is Anti-Fibrotic in Systemic Sclerosis.
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Henderson, John, Dayalan Naidu, Sharadha, Dinkova-Kostova, Albena T., Przyborski, Stefan, Stratton, Richard, and O′Reilly, Steven
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SYSTEMIC scleroderma , *TRANSFORMING growth factors-beta , *CONNECTIVE tissue diseases , *NUCLEAR factor E2 related factor , *HEME oxygenase , *FIBROBLASTS , *OXIDOREDUCTASES - Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin fibrosis. Altered metabolism has recently been described in autoimmune diseases and SSc. Itaconate is a product of the Krebs cycle intermediate cis-aconitate and is an immunomodulator. This work examines the role of the cell-permeable derivative of itaconate, 4-octyl itaconate (4-OI), in SSc. SSc and healthy dermal fibroblasts were exposed to 4-OI. The levels of collagen Nrf2-target genes and pro-inflammatory cytokines interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) were determined. Levels of reactive oxygen species (ROS) as well as the gene expression of collagen and Cellular Communication Network Factor 2 (CCN2) were measured after transforming growth factor beta 1 (TGF-β1) stimulation in the presence or absence of 4-OI. Wild-type or Nrf2-knockout (Nrf2-KO) mouse embryonic fibroblasts (MEFs) were also treated with 4-OI to determine the role of Nrf2 in 4-OI-mediated effects. 4-OI reduced the levels of collagen in SSc dermal fibroblasts. Incubation with 4-OI led to activation of Nrf2 and its target genes heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). 4-OI activated antioxidant response element (ARE)-dependent gene expression, reduced inflammatory cytokine release and reduced TGF-β1-induced collagen and ROS production in dermal fibroblasts. The effects of 4-OI are dependent on Nrf2. The cell-permeable derivative of itaconate 4-OI is anti-fibrotic through upregulation of Nrf2 and could be a potential therapeutic option in an intractable disease. [ABSTRACT FROM AUTHOR]
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- 2021
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155. Targeting pro-fibrotic macrophages with bioactive self-assembly peptides to retard kidney fibrosis - know thyself.
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O'Reilly S
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- Humans, Animals, Kidney Diseases pathology, Kidney pathology, Macrophages immunology, Macrophages metabolism, Macrophages drug effects, Fibrosis, Peptides
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- 2024
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156. The Novel Cytokine Interleukin-41/Meteorin-like Is Reduced in Diffuse Systemic Sclerosis.
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Freedman P, Schock B, and O'Reilly S
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- Adult, Aged, Female, Humans, Male, Middle Aged, Cytokines metabolism, Fibroblasts metabolism, Fibroblasts pathology, Scleroderma, Diffuse pathology, Scleroderma, Diffuse metabolism, Scleroderma, Diffuse blood, Scleroderma, Diffuse genetics, Scleroderma, Systemic pathology, Scleroderma, Systemic metabolism, Scleroderma, Systemic blood, TOR Serine-Threonine Kinases metabolism, Interleukins metabolism, Skin pathology, Skin metabolism
- Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a triad of features that include vascular abnormalities, inflammation and skin and lung fibrosis. At the core of the disease is the activation of myofibroblasts from quiescent fibroblasts and this can be modified by various cytokines. IL-41 is a recently described cytokine that was initially characterised as an adipokine as it was highly expressed in adipocytes and adipose tissue. However, it has recently been identified as being widely expressed and has immunomodulatory functions. This study examined the circulating levels of IL-41 and its expression in skin biopsies. We demonstrated significantly reduced levels of IL-41 in diffuse SSc that was also mirrored in the skin of SSc patients. AMPK has been proposed as a downstream target of IL-41, so we also measure mammalian target of rapamycin in skin and found that this is elevated in SSc patients. We speculate that IL-41 maybe an antifibrotic cytokine and its reduction may facilitate the activation of fibroblasts.
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- 2024
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157. Striking senescence with sodium transporter inhibition.
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Schock B and O'Reilly S
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Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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158. Senescence and tissue fibrosis: opportunities for therapeutic targeting.
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O'Reilly S, Tsou PS, and Varga J
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Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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159. Emerging therapeutic targets in systemic sclerosis.
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O'Reilly S
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- Animals, Fibrosis, Signal Transduction, Scleroderma, Systemic drug therapy, Scleroderma, Systemic metabolism, Autoimmune Diseases
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Systemic sclerosis is an autoimmune connective tissue disease which is characterised by vascular perturbations, inflammation, and fibrosis. Although huge progress recently into the underlying molecular pathways that are perturbed in the disease, currently no therapy exists that targets the fibrosis element of the disease and consequently there is a huge unmet medical need. Emerging studies reveal new dimensions of complexity, and multiple aberrant pathways have been uncovered that have shed light on disturbed signalling in the disease, primarily in inflammatory pathways that can be targeted with repurposed drugs. Pre-clinical animal models using these inhibitors have yielded proof of concept for targeting these signalling systems and progressing to clinical trials. This review will examine the recent evidence of new perturbed pathways in SSc and how these can be targeted with new or repurposed drugs to target a currently intractable disease., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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160. S100A4 a classical DAMP as a therapeutic target in fibrosis.
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O'Reilly S
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- Animals, Fibrosis, Myofibroblasts, Signal Transduction, Humans, Neoplasms, Scleroderma, Systemic
- Abstract
Fibrosis regardless of aetiology is characterised by persistently activated myofibroblasts that are contractile and secrete excessive amounts of extracellular matrix molecules that leads to loss of organ function. Damage-Associated Molecular Patterns (DAMPs) are endogenous host-derived molecules that are released from cells dying or under stress that can be triggered by a variety of insults, either chemical or physical, leading to an inflammatory response. Among these DAMPs is S100A4, part of the S100 family of calcium binding proteins that participate in a variety of cellular processes. S100A4 was first described in context of cancer as a pro-metastatic factor. It is now appreciated that aside from its role in cancer promotion, S100A4 is intimately involved in tissue fibrosis. The extracellular form of S100A4 exerts its effects through multiple receptors including Toll-Like Receptor 4 and RAGE to evoke signalling cascades involving downstream mediators facilitating extracellular matrix deposition and myofibroblast generation and can play a role in persistent activation of myofibroblasts. S100A4 may be best understood as an amplifier of inflammatory and fibrotic processes. S100A4 appears critical in systemic sclerosis pathogenesis and blocking the extracellular form of S100A4 in vivo in various animal models of disease mitigates fibrosis and may even reverse established disease. This review appraises S100A4's position as a DAMP and its role in fibrotic conditions and highlight therapeutically targeting this protein to halt fibrosis, suggesting that it is a tractable target., Competing Interests: Declaration of competing interest SOR is a member of the scientific advisory board of ARXX therapeutics and received payment., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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161. Interleukin-11 and its eminent role in tissue fibrosis: a possible therapeutic target.
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O'Reilly S
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- Animals, Fibrosis, Cytokines, Signal Transduction, Interleukin-33, Interleukin-11, Interleukin-6
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Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes IL-6 and oncostatin-M. Initially described for its role in platelet generation, it is now appreciated that this cytokine has multiple functions. Recently it has been found that IL-11 is critical in fibrosis in multiple different organ systems and systemically as in the autoimmune disease systemic sclerosis. Animal models of fibrosis have determined that animals with IL-11 receptor deletions have retarded fibrosis and that in wild-type animals IL-11 is found at the organ of fibrosis. Recent evidence suggests that IL-11 may be a master regulator of fibrosis regardless of end target organ. With the development of neutralizing antibodies targeting the cytokine in pre-clinical models this could be a possible therapeutic, in a disease in which no specific therapies exist. This review appraises the evidence of the role of IL-11 in tissue fibrosis, its signalling properties, and therapeutic targeting. The review ends with an appraisal of indications for which IL-11 modulation is targeted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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162. Elevated interleukin-11 in systemic sclerosis and role in disease pathogenesis.
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Steadman T and O'Reilly S
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- Humans, Interleukin-11 metabolism, Interleukin-33 metabolism, Alarmins metabolism, Fibrosis, Cytokines metabolism, Fibroblasts pathology, Skin pathology, Scleroderma, Systemic, Scleroderma, Diffuse pathology, Lung Diseases, Interstitial pathology
- Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin-11 (IL-11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor-β (TGF-β1). The objective of this study was to quantify the serum levels of IL-11 in early diffuse SSc patients. Also, if IL-11 could regulate the alarmin IL-33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL-11 was quantified by specific commercial ELISA compared to healthy control (n = 17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL-11. At specific early and late time points the supernatant was quantified for the alarmin IL-33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL-11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL-33 cytokine release into the cell media. IL-11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL-11 could be a possible biomarker of ILD in SSc. It was also found that IL-11 led to release of the cytokine alarmin IL-33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis., (© 2023 Japanese Dermatological Association.)
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- 2023
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163. Senescence in diffuse systemic sclerosis is elevated and may play a role in fibrosis.
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O'Reilly S
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- 2023
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164. At the crossroads of inflammation and fibrosis: epiregulin.
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O'Reilly S
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- Humans, Epiregulin, Fibroblasts, Fibrosis, Intercellular Signaling Peptides and Proteins, Skin pathology, Inflammation pathology, Scleroderma, Systemic pathology
- Abstract
Competing Interests: Competing interests: None declared.
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- 2023
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165. Epigenetics as a versatile regulator of fibrosis.
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Liu Y, Wen D, Ho C, Yu L, Zheng D, O'Reilly S, Gao Y, Li Q, and Zhang Y
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- Humans, Extracellular Matrix genetics, Protein Processing, Post-Translational, Research Personnel, Epigenesis, Genetic, DNA Methylation genetics
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Fibrosis, a process caused by excessive deposition of extracellular matrix (ECM), is a common cause and outcome of organ failure and even death. Researchers have made many efforts to understand the mechanism of fibrogenesis and to develop therapeutic strategies; yet, the outcome remains unsatisfactory. In recent years, advances in epigenetics, including chromatin remodeling, histone modification, DNA methylation, and noncoding RNA (ncRNA), have provided more insights into the fibrotic process and have suggested the possibility of novel therapy for organ fibrosis. In this review, we summarize the current research on the epigenetic mechanisms involved in organ fibrosis and their possible clinical applications., (© 2023. The Author(s).)
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- 2023
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166. Toll-like receptor triggering in systemic sclerosis: time to target.
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O'Reilly S
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- Humans, Signal Transduction, Fibrosis, Inflammation, Toll-Like Receptors, Scleroderma, Systemic
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SSc is an autoimmune disease that has features of vascular abnormalities, inflammation and skin and lung fibrosis. Toll-like receptors (TLRs) are sentinel receptors that serve to recognize pathogens or internal danger signals leading to downstream signalling pathways that ultimately lead to inflammation and modification of adaptive immunity. Inflammation and fibrosis appear intricately connected in this disease and TLR ligation on fibroblasts can directly activate these cells to produce copious amounts of collagen, a hallmark of disease. The presence of damage-associated molecular patterns in association with fibrosis has been highlighted. Given their prominent role in disease, this review discusses the evidence of their expression and role in disease pathogenesis and possible therapeutic intervention to mitigate fibrosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2023
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167. Interleukin-36α is elevated in diffuse systemic sclerosis and may potentiate fibrosis.
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O'Reilly S
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- Cytokines metabolism, Fibroblasts metabolism, Fibrosis, Humans, Interleukin-1 metabolism, Interleukins metabolism, Skin metabolism, Interleukin-1 blood, Scleroderma, Diffuse metabolism, Scleroderma, Diffuse pathology, Scleroderma, Systemic metabolism
- Abstract
Systemic sclerosis (SSc) is an autoimmune prototypical connective tissues disease that results in alterations in vasculature, inflammation and fibrosis of the skin. Interleukin-1 family cytokines has been implicated in the disease including IL-1. IL-36α is an IL-1 family member that is clearly implicated in psoriatic skin disease but its role in systemic sclerosis disease is not clear. The aim of this work is to evaluate the levels and role of IL-36α in systemic sclerosis. Early diffuse SSc patients sera was isolated along with healthy controls and IL-36 levels quantified by ELISA. In vitro analysis was also undertaken with primary dermal fibroblasts with recombinant IL-36α and keratinocyte cells were also incubated with IL-36α. Cytokines were measured by ELISA. Serum IL-36 was significantly elevated compared to healthy controls. Elevated neutrophil elastase was also elevated in the matched sera. IL-36 was not directly pro-fibrotic in dermal fibroblasts but did induce pro-inflammatory cytokines that were dependant on the MAPK pathway for their release. IL-36α also led to release of CCL20 and CCL2 in keratinocytes which may potentiate fibrosis. IL-36α is elevated in SSc serum and whilst not directly pro-fibrotic it may through keratinocytes, potentiate fibrosis through keratinocyte-immune fibroblast cross-talk., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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168. Keeping time on liver fibrosis.
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O'Reilly S
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- Humans, Liver pathology, Liver Cirrhosis pathology
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- 2022
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169. Metabolic perturbations in systemic sclerosis.
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O'Reilly S
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- Fibroblasts pathology, Fibrosis, Humans, Skin pathology, Scleroderma, Systemic pathology, Vascular Diseases
- Abstract
Purpose of Review: The aim of this review is to evaluate the recent evidence of the role of metabolism in systemic sclerosis (SSc), highlighting specific aberrations and to appraise the feasibility of targeting these therapeutically., Recent Findings: SSc is an autoimmune disease that is characterised by three facets: vascular problems, inflammation, and fibrosis. The fibrosis primarily affects the skin and lungs and currently, no antifibrotic treatment has been found effective. In recent years a renaissance in metabolism research has begun with renewed vigour in the role of metabolism in disease, particularly in the immune system. Alterations in glycolysis and utilisation of specific metabolic pathways in specific cell types have been associated with specific diseases. Most recently alterations in glycolysis and glutaminolysis have been determined in SSc fibroblasts mediating fibrosis. Reduced nicotinamide adenine dinucleotide levels have also been described in SSc., Summary: Specific metabolic aberrations have been described in SSc and this may lead to novel therapeutic targets in this disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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170. Gremlin: a complex molecule regulating wound healing and fibrosis.
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O'Reilly S
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- Animals, Humans, Fibrosis physiopathology, Intercellular Signaling Peptides and Proteins metabolism, Wound Healing
- Abstract
Gremlin-1 is part of the TGF-β superfamily and is a BMP antagonist that blocks BMP signalling to precisely control BMP gradients. Gremlin-1 is primarily involved in organogenesis and limb patterning however, has recently been described as being involved in fibrotic diseases. Initially described as a key factor involved in diabetic kidney fibrosis due to being induced by high glucose, it has now been described as being associated with lung, liver, eye, and skin fibrosis. This suggests that it is a key conserved molecule mediating fibrotic events irrespective of organ. It appears that Gremlin-1 may have effects mediated by BMP-dependent and independent pathways. The aim of this review is to evaluate the role of Gremlin-1 in fibrosis, its mechanisms and if this can be targeted therapeutically in fibrotic diseases, which currently have very limited treatment options and are highly prevalent., (© 2021. Crown.)
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- 2021
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171. IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFβ-mediated activation of dermal fibroblasts.
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Adami E, Viswanathan S, Widjaja AA, Ng B, Chothani S, Zhihao N, Tan J, Lio PM, George BL, Altunoglu U, Ghosh K, Paleja BS, Schafer S, Reversade B, Albani S, Ling ALH, O'Reilly S, and Cook SA
- Subjects
- Biomarkers blood, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Humans, Interleukin-11 Receptor alpha Subunit biosynthesis, Scleroderma, Systemic genetics, Scleroderma, Systemic pathology, Signal Transduction, Gene Expression Regulation, Interleukin-11 blood, Interleukin-11 Receptor alpha Subunit genetics, MAP Kinase Signaling System genetics, RNA genetics, Scleroderma, Systemic blood, Skin pathology
- Abstract
Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls., Methods: We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping., Results: In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK., Conclusions: These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2021
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172. Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential.
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Tsou PS, Varga J, and O'Reilly S
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- DNA Methylation, Endothelial Cells metabolism, Epigenesis, Genetic physiology, Epigenomics methods, Epigenomics trends, Fibroblasts metabolism, Fibrosis drug therapy, Fibrosis genetics, Fibrosis metabolism, Gene Expression Regulation genetics, Histone Code genetics, Humans, Immune System cytology, Immune System metabolism, Immune System physiopathology, RNA, Untranslated genetics, Epigenesis, Genetic genetics, Scleroderma, Systemic drug therapy, Scleroderma, Systemic genetics, Scleroderma, Systemic metabolism, Scleroderma, Systemic physiopathology
- Abstract
Systemic sclerosis (SSc) is a prototypical inflammatory fibrotic disease involving inflammation, vascular abnormalities and fibrosis that primarily affect the skin and lungs. The aetiology of SSc is unknown and its pathogenesis is only partially understood. Of all the rheumatic diseases, SSc carries the highest all-cause mortality rate and represents an unmet medical need. A growing body of evidence implicates epigenetic aberrations in this intractable disease, including specific modifications affecting the three main cell types involved in SSc pathogenesis: immune cells, endothelial cells and fibroblasts. In this Review, we discuss the latest insights into the role of DNA methylation, histone modifications and non-coding RNAs in SSc and how these epigenetic alterations affect disease features. In particular, histone modifications have a role in the regulation of gene expression pertinent to activation of fibroblasts to myofibroblasts, governing their fate. DNA methyltransferases are crucial in disease pathogenesis by mediating methylation of DNA in specific promoters, regulating expression of specific pathways. We discuss targeting of these enzymes for therapeutic gain. Innovative epigenetic therapy could be targeted to treat the disease in a precision epigenetics approach., (© 2021. Springer Nature Limited.)
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- 2021
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173. Circulating Gremlin-1 is elevated in systemic sclerosis patients.
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O'Reilly S
- Abstract
Introduction: Systemic sclerosis is an autoimmune connective tissue disease in which there is activation of the immune system, vascular disease and fibrosis. Activation of quiescent fibroblasts to myofibroblasts is key to disease pathogenesis. Gremlin-1 is a bone morphogenetic protein antagonist which is important in development and we recently reported in skin fibrosis. The aim of this study was to determine the serum circulating levels of Gremlin-1 in early diffuse systemic sclerosis., Methods: Twenty-one early diffuse systemic sclerosis patients (less than 2 years from first non-Raynaud's symptom) were included and age and sex-matched healthy controls. Serum was isolated from blood and measured with a specific enzyme-linked immunoassay for Gremlin-1. Clinical variables were also measured., Results: Significantly elevated Gremlin-1 was found in sera of early diffuse systemic sclerosis patients ( p < 0.001). In patients with interstitial lung disease, this compared to systemic sclerosis without evidence of interstitial lung disease, Gremlin-1 was significantly elevated ( p < 0.0007). A correlation was found between circulating Gremlin-1 and modified Rodnan Skin Score, albeit weak., Discussion: In early diffuse systemic sclerosis patients, elevated Gremlin-1 is found in serum. This is particularly prominent in systemic sclerosis-associated interstitial lung disease. This suggests that Gremlin-1 may be a biomarker for systemic sclerosis interstitial lung disease., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2021.)
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- 2021
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174. The emerging role of metabolism in fibrosis.
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Henderson J and O'Reilly S
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- Energy Metabolism, Humans, Oxidation-Reduction, Fibrosis metabolism, Glycolysis, Neoplasms metabolism
- Abstract
The metabolic shift that cancer cells undergo towards aerobic glycolysis was identified as a defining feature in tumours almost 100 years ago; however, it has only recently become apparent that similar metabolic reprogramming is a key feature in other diseases - with fibrosis now entering the fray. In this perspective, an overview of the recent evidence implicating increased glycolysis and glutaminolysis as mediators of fibrosis is presented, with a particular emphasis on the novel therapeutic possibilities this introduces. Furthermore, the impact that metabolic reprogramming has on redox homeostasis is discussed, providing an insight into how this often-overlooked mechanism may drive the pathogenesis., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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175. Bone Morphogenetic Protein Antagonist Gremlin-1 Increases Myofibroblast Transition in Dermal Fibroblasts: Implications for Systemic Sclerosis.
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Duffy L, Henderson J, Brown M, Pryzborski S, Fullard N, Summa L, Distler JHW, Stratton R, and O'Reilly S
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Objective: Systemic Sclerosis is an autoimmune connective tissue disease which results in fibrosis of the skin and lungs. The disease is characterized by activation of myofibroblasts but what governs this is unknown. Gremlin-1 is a BMP antagonist that is developmentally regulated and we sought to investigate its role in Systemic Sclerosis., Methods: Dermal fibroblasts were transfected with Grem1pcDNA3.1 expression vectors or empty vectors. Various markers of myofibroblasts were measured at the mRNA and protein levels. Scratch wound assays were also performed. Media Transfer experiments were performed to evaluate cytokine like effects. Various inhibitors of TGF-β signaling and MAPK signaling were used post-transfection. siRNA to Gremlin-1 in SSc dermal fibroblasts were performed to evaluate the role of Gremlin-1. Different cytokines were incubated with fibroblasts and Gremlin-1 measured. Bleomycin was used as model of fibrosis and immunohistochemistry performed., Results: Overexpression of Gremlin-1 was achieved in primary dermal fibroblasts and lead to activation of quiescent cells to myofibroblasts indicated by collagen and α-Smooth muscle actin. Overexpression also led to functional effects. This was associated with increased TGF-β1 levels and SBE luciferase activity but not increased Thrombospondin-1 expression. Inhibition of Gremlin-1 overexpression cells with antibodies to TGF-β1 but not isotype controls led to reduced collagen and various TGF-β pathway chemical inhibitors also led to reduced collagen levels. In SSc cells siRNA mediated reduction of Gremlin-1 reduced collagen expression and CTGF gene and protein levels in these cells. IL-13 did not lead to elevated Gremlin-1 expression nor did IL-11. Gremlin-1 was elevated in an animal model of fibrosis compared to NaCl-treated mice., Conclusion: Gremlin-1 is a key regulator of myofibroblast transition leading to enhanced ECM deposition. Strategies that block Gremlin-1 maybe a possible therapeutic target in fibrotic diseases such as SSc., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Duffy, Henderson, Brown, Pryzborski, Fullard, Summa, Distler, Stratton and O’Reilly.)
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- 2021
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176. cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis.
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Worrell JC, Leslie J, Smith GR, Zaki MYW, Paish HL, Knox A, James ML, Cartwright TN, O'Reilly S, Kania G, Distler O, Distler JHW, Herrick AL, Jeziorska M, Borthwick LA, Fisher AJ, Mann J, Mann DA, and Oakley F
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- Animals, Extracellular Matrix metabolism, Fibrosis, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Lung metabolism, Lung pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Scleroderma, Systemic pathology, Fibroblasts metabolism, Proto-Oncogene Proteins c-rel metabolism, Scleroderma, Systemic metabolism
- Abstract
Objectives: NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc., Methods: Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls., Results: cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts., Conclusion: cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2020
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177. Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis.
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Henderson J, Duffy L, Stratton R, Ford D, and O'Reilly S
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- Biomarkers, Cells, Cultured, Collagen metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Fibrosis, Glycolysis drug effects, Humans, Models, Biological, Receptors, Transforming Growth Factor beta metabolism, Scleroderma, Systemic pathology, Smad Proteins metabolism, Transforming Growth Factor beta1 metabolism, Transforming Growth Factor beta1 pharmacology, Cellular Reprogramming, Energy Metabolism drug effects, Glutamine metabolism, Myofibroblasts metabolism, Scleroderma, Systemic etiology, Scleroderma, Systemic metabolism
- Abstract
Systemic Sclerosis (SSc) is a rare fibrotic autoimmune disorder for which no curative treatments currently exist. Metabolic remodelling has recently been implicated in other autoimmune diseases; however, its potential role in SSc has received little attention. Here, we aimed to determine whether changes to glycolysis and glutaminolysis are important features of skin fibrosis. TGF-β1, the quintessential pro-fibrotic stimulus, was used to activate fibrotic pathways in NHDFs in vitro. Dermal fibroblasts derived from lesions of SSc patients were also used for in vitro experiments. Parameters of glycolytic function were assessed using by measuring extracellular acidification in response to glycolytic activators/inhibitors, whilst markers of fibrosis were measured by Western blotting following the use of the glycolysis inhibitors 2-dg and 3PO and the glutaminolysis inhibitor G968. Succinate was also measured after TGF-β1 stimulation. Itaconate was added to SSc fibroblasts and collagen examined. TGF-β1 up-regulates glycolysis in dermal fibroblasts, and inhibition of glycolysis attenuates its pro-fibrotic effects. Furthermore, inhibition of glutamine metabolism also reverses TGF-β1-induced fibrosis, whilst glutaminase expression is up-regulated in dermal fibroblasts derived from SSc patient skin lesions, suggesting that enhanced glutamine metabolism is another aspect of the pro-fibrotic metabolic phenotype in skin fibrosis. TGF-β1 was also able to enhance succinate production, with increased succinate shown to be associated with increased collagen expression. Incubation of SSc cells with itaconate, an important metabolite, reduced collagen expression. TGF-β1 activation of glycolysis is a key feature of the fibrotic phenotype induced by TGF-B1 in skin cells, whilst increased glutaminolysis is also evident in SSc fibroblasts., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
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- 2020
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178. Bi-directional communication: Conversations between fibroblasts and immune cells in systemic sclerosis.
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Worrell JC and O'Reilly S
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- Animals, B-Lymphocytes metabolism, Cytokines metabolism, Disease Models, Animal, Feedback, Physiological, Humans, Immunity, Innate, Myofibroblasts metabolism, Scleroderma, Systemic blood, Signal Transduction immunology, T-Lymphocytes metabolism, B-Lymphocytes immunology, Cell Communication immunology, Myofibroblasts immunology, Scleroderma, Systemic immunology, T-Lymphocytes immunology
- Abstract
Systemic Sclerosis (SSc) is an autoimmune idiopathic connective tissue disease, characterized by aberrant fibro-proliferative and inflammatory responses, causing fibrosis of multiple organs. In recent years the interactions between innate and adaptive immune cells with resident fibroblasts have been uncovered. Cross-talk between immune and stromal cells mediates activation of stromal cells to myofibroblasts; key cells in the pathophysiology of fibrosis. These cells and their cytokines appear to mediate their effects in both a paracrine and autocrine fashion. This review examines the role of innate and adaptive immune cells in SSc, focusing on recent advances that have illuminated our understanding of ongoing bi-directional communication between immune and stromal cells. Finally, we appraise current and future therapies and how these may be useful in a disease that currently has no specific disease modifying treatment., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2020
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179. Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma.
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Yaseen B, Lopez H, Taki Z, Zafar S, Rosario H, Abdi BA, Vigneswaran S, Xing F, Arumalla N, Black S, Ahmad S, Kumar K, Gul R, Scolamiero L, Morris S, Bowman A, Stainer A, Rice A, Stock C, Renzoni E, Denton CP, Venturini C, Brown M, O'Reilly S, and Stratton R
- Subjects
- Animals, Epigenesis, Genetic immunology, Fibroblasts metabolism, Fibrosis immunology, Humans, Mice, Mice, Inbred BALB C, Interleukins immunology, Lung immunology, Lung pathology, Receptors, Interleukin immunology, Scleroderma, Systemic immunology, Scleroderma, Systemic pathology, Skin immunology
- Abstract
Objectives: Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis., Methods: IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma., Results: IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA., Conclusion: IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2020
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180. Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis.
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Taki Z, Gostjeva E, Thilly W, Yaseen B, Lopez H, Mirza M, Hassuji Z, Vigneswaran S, Ahmed Abdi B, Hart A, Arumalla N, Thomas G, Denton CP, Suleman Y, Liu H, Venturini C, O'Reilly S, Xu S, and Stratton R
- Subjects
- Adult, Biopsy, Cell Culture Techniques, Female, Fibroblasts physiology, Humans, Male, Skin cytology, Skin pathology, Cell Transdifferentiation physiology, Cellular Microenvironment physiology, Mesenchymal Stem Cells pathology, Scleroderma, Diffuse pathology, Scleroderma, Systemic pathology
- Abstract
Objective: In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation., Methods: Skin biopsy material from patients with recent-onset diffuse SSc was examined by collagenase spread of 1-mm-thick surface-parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose-derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next-generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel., Results: MSC-like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin-31, enhanced osteogenic commitment (calcinosis)., Conclusion: Dividing MSC-like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state., (© 2020, American College of Rheumatology.)
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- 2020
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181. Current and Potential New Targets in Systemic Sclerosis Therapy: a New Hope.
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Hinchcliff M and O'Reilly S
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- Clinical Trials as Topic, Fibroblasts, Fibrosis, Humans, Indoles, Lung Diseases, Interstitial, Receptor, Cannabinoid, CB2 agonists, Scleroderma, Systemic drug therapy
- Abstract
Purpose of Review: Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is an activation of fibroblast to a myofibroblast that secretes huge amounts of extracellular matrix. Currently, no treatment exists that modifies the fibrosis elements and new therapeutic targets are badly needed. This review examines the current state of treatments and emerging therapeutics., Recent Findings: Nintedanib was found to significantly reduce the rate of decline in SSc associated FVC, although it has no benefit on skin fibrosis. New cannabinoid receptor2 agonist has shown superb effects in phase II and results in phase III are anticipated. Other targets are currently being tested in clinical trials and new targets that are yet to be tested are increasing in the SSc literature. Nintedanib is now licenced for SSc interstitial lung disease but this does not modify the skin fibrosis. Current ongoing trials will determine the role of various targets. New targets are emerging as we gain a deeper understanding of disease pathogenesis.
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- 2020
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182. The Role of Epigenetic Modifications in Systemic Sclerosis: A Druggable Target.
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Henderson J, Distler J, and O'Reilly S
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- Animals, Autoimmunity genetics, Biomarkers, DNA Methylation, DNA Repair, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Humans, MicroRNAs genetics, Molecular Targeted Therapy, RNA, Messenger genetics, RNA, Untranslated genetics, Scleroderma, Systemic drug therapy, Scleroderma, Systemic metabolism, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Disease Susceptibility, Epigenesis, Genetic, Gene Expression Regulation, Scleroderma, Systemic etiology
- Abstract
Systemic sclerosis (SSc) is a rare autoimmune disorder characterised by skin fibrosis that often also affects internal organs, eventually resulting in mortality. Although management of the symptoms has extended lifespan, patients still suffer from poor quality of life, hence the need for improved therapies. Development of efficacious treatments has been stymied by the unknown aetiology, although recent advancements suggest a potentially key role for epigenetics - the regulation of gene expression by noncoding RNAs and chemical modifications to DNA or DNA-associated proteins. Herein, the evidence implicating epigenetics in the pathogenesis of SSc is discussed with an emphasis on the therapeutic potential this introduces to the field - particularly the repurposing of epigenetic targeting cancer therapeutics and newly emerging miRNA-based strategies., (Copyright © 2019. Published by Elsevier Ltd.)
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- 2019
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183. Bioengineering the microanatomy of human skin.
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Roger M, Fullard N, Costello L, Bradbury S, Markiewicz E, O'Reilly S, Darling N, Ritchie P, Määttä A, Karakesisoglou I, Nelson G, von Zglinicki T, Dicolandrea T, Isfort R, Bascom C, and Przyborski S
- Subjects
- Basement Membrane cytology, Basement Membrane ultrastructure, Cell Differentiation, Cells, Cultured, Dermis cytology, Dermis ultrastructure, Epidermis ultrastructure, Extracellular Matrix Proteins metabolism, Fibroblasts metabolism, Humans, In Vitro Techniques methods, Keratinocytes metabolism, Microscopy, Electron, Skin anatomy & histology, Skin ultrastructure, Tissue Engineering methods
- Abstract
Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell-based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal-derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In-depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum, specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin., (© 2019 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)
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- 2019
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184. Innate immunity and Toll-like receptor signaling in the pathogenesis of scleroderma: advances and opportunities for therapy.
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Brown M and O'Reilly S
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- Animals, Humans, Signal Transduction immunology, Immunity, Innate immunology, Immunotherapy methods, Scleroderma, Localized immunology, Scleroderma, Localized pathology, Scleroderma, Localized therapy, Toll-Like Receptors immunology
- Abstract
Purpose of Review: Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which inflammation and cytokine dysregulation leads to skin fibrosis. Toll-like receptors (TLRs) are conserved pattern recognition receptors, recognizing pathogens danger-associated molecular patterns (DAMPs) that elicit a cascade of proinflammatory signaling. Recently, TLRs have been found to be critically important in SSc pathogenesis, with increased levels of the TLRs and their ligands present in the disease. Animal models have also been pivotal in delineating the role of these innate immune receptors in SSc. This current review examines the role of TLRs and the most recent evidence of the role of DAMPs and how these may be exploited therapeutically., Recent Findings: Increasingly, studies have demonstrated the key roles of TLR4 and other intracellular TLRs in mediating fibrosis in SSc patients and animal models. TLR4 activation appears a key point and novel DAMPs, expressed upon tissue damage, appear critical in mediating the profibrotic effect through a downstream enhancement of transforming growth factor β. Deletion of Tenascin-C or a splice variant of fibronectin ameliorates animal models of skin fibrosis. Intracellular, nucleic acid sensing, TLR8 is critical in activating macrophages to secrete profibrotic molecules. The mechanism involves histone modification through epigenetic modifying enzymes., Summary: TLRs are key therapeutic targets in SSc.
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- 2018
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185. Targeting the TLR4-MD2 axis in systemic sclerosis.
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O'Reilly S and van Laar JM
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- Fibroblasts, Fibrosis, Humans, Lipopolysaccharides, Skin, Scleroderma, Systemic, Toll-Like Receptor 4
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- 2018
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186. Toll Like Receptors in systemic sclerosis: An emerging target.
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O'Reilly S
- Subjects
- Animals, Autoimmunity, Humans, Immunity, Innate, Molecular Targeted Therapy, Pathogen-Associated Molecular Pattern Molecules metabolism, Scleroderma, Systemic therapy, Signal Transduction, Cytokines metabolism, Scleroderma, Systemic immunology, Toll-Like Receptors metabolism
- Abstract
Pattern Recognition Receptors are critical receptors that elicit an immune response upon their activation that culminates in activation of NF-KB and cytokine secretion. Key among these receptors are the Toll-Like Receptors (TLRs). These evolutionary conserved receptors form a key part in the defence against various pathogens and comprise a key part of the innate immune system. Systemic sclerosis is an autoimmune disease in which a breach of tolerance has occurred and leads to fulminant autoimmunity, dysregulated cytokines, pro-fibrotic mediators and activation of fibroblasts leading to fibrosis via collagen deposition. It has become apparent in recent years that the innate immune system and specifically TLRs are important in disease pathogenesis; responding to internal ligands to initiate an innate immune response ultimately leading to release of a variety of factors that initiate and perpetuate fibrosis. This review will examine the recent evidence of TLR signalling in systemic sclerosis and the internal danger associated molecules that may mediate the fibrotic cascade. Evaluation of their contribution to disease in systemic sclerosis and possible therapeutic targeting will be discussed., (Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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187. Immunology and systemic sclerosis - Editorial.
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O'Reilly S and Laar JMV
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- Humans, Immunity, Innate, Pathogen-Associated Molecular Pattern Molecules immunology, Signal Transduction, Toll-Like Receptors metabolism, Blood Vessels pathology, Cytokines metabolism, Immune System, Inflammation immunology, Scleroderma, Systemic immunology
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- 2018
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188. Functional Implications of Cross-Linked Actin Networks in Trabecular Meshwork Cells.
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Duffy L and O'Reilly S
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- Actin Cytoskeleton drug effects, Animals, Cattle, Cell Survival drug effects, Cells, Cultured, Collagen Type I chemistry, Connective Tissue Growth Factor genetics, Connective Tissue Growth Factor metabolism, Dexamethasone pharmacology, Enzyme-Linked Immunosorbent Assay, Hydrogen Peroxide analysis, Interleukin-6 analysis, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 2 metabolism, Microscopy, Confocal, Stress, Physiological, Time-Lapse Imaging, Trabecular Meshwork cytology, Trabecular Meshwork metabolism, Trabecular Meshwork pathology, Transforming Growth Factor beta2 analysis, Actin Cytoskeleton physiology, Actins metabolism
- Abstract
Background/aims: The Trabecular meshwork (TM) is the tissue responsible for outflow resistance and therefore intraocular pressure. TM cells contain a contractile apparatus that is composed of actin stress fibres which run parallel to the axis of the cell and are responsible for facilitating contraction. Cross-Linked Actin Networks (CLANs) are polygonal arrangements of actin that form a geodesic network found predominantly in TM cells both in situ and in vitro. The aim of this work is to determine the functional significance of CLANs in TM cells and to assess the effect of mechanical stretch stimulation on the induction (or not) of CLANs., Methods: We used collagen gel contraction models to demonstrate functional impairment of cells when induced to express CLANs in situ. Cyclic mechanical stretch was used to stimulate cells and measure CLANs Results: CLANs inhibited contraction and cyclic mechanical stretch induced CLANs. Furthermore, we also demonstrated that using shape alone we could predict the appearance of CLANs using a simple light microscopy technique., Conclusion: Taken together we have now shown, for the first time, a functional deficit In TM cells with CLANs Furthermore that shape alone can predict the appearance of CLAN containing cells. CLANs can now be linked to a functional effect and may underlie the appearance of CLANs with the pathology of primary open angle glaucoma (POAG)., (© 2018 The Author(s). Published by S. Karger AG, Basel.)
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- 2018
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189. Epigenetics in fibrosis.
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O'Reilly S
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- Animals, DNA Methylation genetics, Epigenesis, Genetic, Histones metabolism, Humans, Inheritance Patterns genetics, Myofibroblasts metabolism, Myofibroblasts pathology, Fibrosis genetics
- Abstract
Fibrosis is a common and important disease. It is a pathological state due to excessive scar formation mediated by an increase in activated fibroblasts that express alpha smooth muscle actin and copious amounts of extracellular matrix molecules. Epigenetics is an area of research that encompasses three main mechanisms: methylation, histone modifications to the tails of histones and also non-coding RNAs including long and short non-coding RNAs. These three mechanisms all seek to regulate gene expression without a change in the underlying DNA sequence. In recent years an explosion of research, aided by deep sequencing technology becoming available, has demonstrated a role for epigenetics in fibrosis, either organ specific like lung fibrosis or more widespread as in systemic sclerosis. While the great majority of epigenetic work in fibrosis is centered on histone codes, more recently the non-coding RNAs have been examined in greater detail. It is known that one modification can affect the other and cross-talk among all three adds a new layer of complexity. This review aims to examine the role of epigenetics in fibrosis, evaluating all three mechanisms, and to suggest possible areas where epigenetics could be targeted therapeutically., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
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- 2017
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190. Innate Immunity in Systemic Sclerosis.
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Dowson C, Simpson N, Duffy L, and O'Reilly S
- Subjects
- Complement System Proteins immunology, Humans, Immunity, Innate, Inflammasomes immunology, Macrophages immunology, Mast Cells immunology, Monocytes immunology, Toll-Like Receptors immunology, Scleroderma, Systemic immunology
- Abstract
Purpose of Review: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease which has defined three hallmarks: Small vessel vasculopathy, production of autoantibodies and fibroblast dysfunction. The exact aetiology of the disease remains unknown, due to the complex nature of the cellular signalling pathways involved. However, there is strong and consistent evidence that the innate system, in particular toll-like receptor signalling, is contributing to the progression and perhaps onset of systemic sclerosis. In light of this evidence, this review examines the role of innate immunity in systemic sclerosis and where appropriate suggests avenues for therapeutic modulation in SSc., Recent Findings: Multiple lines of evidence suggest that Toll-like receptors (TLRs) are dysregulated and emerging evidence suggests that many endogenous ligands are also elevated in the disease leading to 'sterile inflammation' and ultimately the induction of fibrosis. Currently, no effective therapy exists and exploiting the innate immune system perturbation may be one possible avenue. Innate immune dysregulation is key in SSc pathogenesis and may represent a novel target.
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- 2017
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191. Toll-like receptors in the pathogenesis of autoimmune diseases: recent and emerging translational developments.
- Author
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Duffy L and O'Reilly SC
- Abstract
Autoinflammatory diseases are defined as the loss of self-tolerance in which an inflammatory response to self-antigens occurs, which are a significant global burden. Toll-like receptors are key pattern recognition receptors, which integrate signals leading to the activation of transcription factors and ultimately proinflammatory cytokines. Recently, it has become apparent that these are at the nexus of autoinflammatory diseases making them viable and attractive drug targets. The aim of this review was to evaluate the role of innate immunity in autoinflammatory conditions alongside the role of negative regulation while suggesting possible therapeutic targets.
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- 2016
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192. Histone Demethylation and Toll-like Receptor 8-Dependent Cross-Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra-2.
- Author
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Ciechomska M, O'Reilly S, Przyborski S, Oakley F, Bogunia-Kubik K, and van Laar JM
- Subjects
- Animals, Epigenesis, Genetic, Humans, Methylation, Mice, Middle Aged, Cell Transdifferentiation, Fibroblasts cytology, Fos-Related Antigen-2 physiology, Histones metabolism, Monocytes physiology, Receptor Cross-Talk, Scleroderma, Systemic metabolism, Scleroderma, Systemic pathology, Tissue Inhibitor of Metalloproteinase-1 physiology, Toll-Like Receptor 8 physiology
- Abstract
Objective: To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP-1) via Fra-2 (an activator protein 1 [AP-1] family member), a novel downstream mediator that promotes fibrogenesis., Methods: AP-1 transcription factors and TIMP-1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra-2 in the regulation of TIMP-1 following treatment with Toll-like receptor 8 (TLR-8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis. Expression of TIMP-1 and Fra-2 was determined in response to TLR-8 treatment and to different histone modifications, including 3'-deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR-8-treated healthy control monocytes., Results: Up-regulation of Fra-2 was detected in bleomycin-challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra-2 and TIMP-1 was correlated in SSc monocytes (P = 0.021). The expression of Fra-1 was significantly reduced (P = 0.037) in SSc monocytes. Inhibiting AP-1 activity reduced TIMP-1 production in TLR-8-stimulated monocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra-2 to the TIMP-1 promoter. Stimulation with DZNep plus TLR-8 enhanced Fra-2 and TIMP-1 expression in healthy control monocytes, whereas TLR-8 plus apicidin repressed Fra-2 and TIMP-1 expression. Finally, healthy control monocytes treated with DZNep plus TLR-8 induced strong production of α-smooth muscle actin in dermal fibroblasts, which was inhibited by TIMP-1-blocking antibody., Conclusion: These data demonstrate a novel role of histone demethylation induced by DZNep on Fra-2-mediated TIMP-1 production by monocytes in the presence of TLR-8 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc., (© 2016, American College of Rheumatology.)
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- 2016
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193. Connective tissue diseases: Nucleosomes and systemic sclerosis.
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O'Reilly S and van Laar JM
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes pathology, Humans, Immunoglobulin G biosynthesis, Immunoglobulin G immunology, Lymphocyte Activation, Mice, Scleroderma, Systemic pathology, Nucleosomes immunology, Scleroderma, Systemic immunology
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- 2016
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194. MicroRNAs in fibrosis: opportunities and challenges.
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O'Reilly S
- Subjects
- Animals, Clinical Trials as Topic methods, Fibrosis pathology, Gene Targeting methods, Humans, Signal Transduction physiology, Fibrosis genetics, Fibrosis metabolism, MicroRNAs biosynthesis, MicroRNAs genetics
- Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that mediate mRNA cleavage, translational repression or mRNA destabilisation and are around 22-25 nucleotides in length via partial complementary binding to the 3' untranslated region in target transcripts. They are master regulators of gene expression. Fibrosis is an important cause of morbidity and mortality in the world, and there are currently no accepted treatments for fibrosis. Many novel miRNAs are now associated with fibrosis, both organ-specific and systemic, as in the prototypical fibrotic disease systemic sclerosis. Recently, the targets of these altered miRNAs have been validated and defined new biochemical pathways. Dysregulated miRNAs are amenable to therapeutic modulation. This review will examine the role of miRNAs in fibrosis and the opportunities and challenges of targeting them.
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- 2016
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195. Synthesis of Bis(oxazoline) Ligands Possessing C-5 gem-Disubstitution and Their Application in Asymmetric Friedel-Crafts Alkylations.
- Author
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O'Reilly S, Aylward M, Keogh-Hansen C, Fitzpatrick B, McManus HA, Müller-Bunz H, and Guiry PJ
- Abstract
A series of eight novel bis(oxazoline) ligands incorporating gem-disubstitution on one of the oxazoline rings were prepared from (S)-valine. These ligands are designed as a cost-effective alternative to similar ligands possessing an oxazolinyl C(5)-tert-butyl group derived from expensive (S)-tert-leucine. Four of the ligands possess a C(4)-gem-dimethyl group and four a C(4)-gem-diphenyl group adjacent to the C(5)-isopropyl substituent. Zinc complexes of ligands 11a-h, along with non-C(4)-gem-disubstituted analogues 1a-g, were effective in the Friedel-Crafts alkylation of both indole (up to 74% ee) and 2-methoxyfuran (up to 95% ee) with a series of nitroalkenes. Three of the ligands (11a-c), an iron dichloride complex of ligand 11d and two zinc dichloride complexes, were characterized by X-ray crystallography, one with ligand 11d and the second a bis-tert-butyl-substituted N-methylamine ligand. A direct comparison of the latter structures clearly illustrates the gem-dimethyl effect.
- Published
- 2015
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196. Role of innate immune system in systemic sclerosis.
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Fullard N and O'Reilly S
- Subjects
- Autoantibodies immunology, Humans, Receptors, Pattern Recognition metabolism, Scleroderma, Systemic metabolism, Signal Transduction immunology, Immunity, Innate immunology, Scleroderma, Systemic immunology, Toll-Like Receptors metabolism
- Abstract
Recognition of microbial or viral compounds is crucial to elicit an immune response and pattern recognition receptors (PRRs) form the first line of defence. An important family of PRRs are the Toll-like receptors (TLRs) with numerous evidences indicating their crucial role in identifying microbial or viral compounds. However, the danger theory, where the innate immune system responds to danger signals such as proteins released during damage or necrosis rather than only non-self is gaining ground. Indeed, TLRs are able to recognise endogenous molecules and have been implicated as key players in numerous autoimmune diseases including systemic sclerosis (SSc). TLR2 is known to be upregulated in SSc and has been shown to respond to the endogenous ligand amyloid A resulting in increased IL-6 secretion. TLR4 is now known to respond to a variety of endogenous ligands including fibronectin, containing alternatively spliced exons encoding type III repeat extra domain (EDA). EDA is only expressed upon tissue damage, and elevated levels can be found in SSc patients, idiopathic pulmonary fibrosis and cardiac allograft fibrosis, while deletion of EDA or TLR4 in mice reduces their fibrotic response. Further, stimulation of TLR8 with single-stranded RNA leads to increased expression of TIMP-1. This has been shown to require both IRAK4 and NF-κB with evidence suggesting autoantibodies bind to RNA to stimulate TIMP-1 production in monocytes. Therefore, TLR-mediated signalling provides numerous potential therapeutic targets for development of therapies for the treatment of multi-systemic autoimmune diseases.
- Published
- 2015
- Full Text
- View/download PDF
197. The c-Rel subunit of NF-κB regulates epidermal homeostasis and promotes skin fibrosis in mice.
- Author
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Fullard N, Moles A, O'Reilly S, van Laar JM, Faini D, Diboll J, Reynolds NJ, Mann DA, Reichelt J, and Oakley F
- Subjects
- Animals, Bleomycin, Cell Differentiation physiology, Cell Proliferation drug effects, Cells, Cultured, Epidermis pathology, Fibrosis, Humans, Keratinocytes cytology, Keratinocytes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B p50 Subunit deficiency, NF-kappa B p50 Subunit metabolism, Proto-Oncogene Proteins c-rel deficiency, Proto-Oncogene Proteins c-rel metabolism, Psoriasis metabolism, Scleroderma, Systemic metabolism, Skin injuries, Skin metabolism, Skin pathology, Tetradecanoylphorbol Acetate pharmacology, Transcription Factor RelA metabolism, Wound Healing physiology, Epidermis metabolism, Homeostasis physiology, Proto-Oncogene Proteins c-rel physiology
- Abstract
The five subunits of transcription factor NF-κB have distinct biological functions. NF-κB signaling is important for skin homeostasis and aging, but the contribution of individual subunits to normal skin biology and disease is unclear. Immunohistochemical analysis of the p50 and c-Rel subunits within lesional psoriatic and systemic sclerosis skin revealed abnormal epidermal expression patterns, compared with healthy skin, but RelA distribution was unaltered. The skin of Nfkb1(-/-) and c-Rel(-/-) mice is structurally normal, but epidermal thickness and proliferation are significantly reduced, compared with wild-type mice. We show that the primary defect in both Nfkb1(-/-) and c-Rel(-/-) mice is within keratinocytes that display reduced proliferation both in vitro and in vivo. However, both genotypes can respond to proliferative stress, with 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation and closure rates of full-thickness skin wounds being equivalent to those of wild-type controls. In a model of bleomycin-induced skin fibrosis, Nfkb1(-/-) and c-Rel(-/-) mice displayed opposite phenotypes, with c-Rel(-/-) mice being protected and Nfkb1(-/-) developing more fibrosis than wild-type mice. Taken together, our data reveal a role for p50 and c-Rel in regulating epidermal proliferation and homeostasis and a profibrogenic role for c-Rel in the skin, and identify a link between epidermal c-Rel expression and systemic sclerosis. Modulating the actions of these subunits could be beneficial for treating hyperproliferative or fibrogenic diseases of the skin., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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198. Interleukin-6, its role in fibrosing conditions.
- Author
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O'Reilly S, Ciechomska M, Cant R, Hügle T, and van Laar JM
- Subjects
- Actins physiology, Animals, Cytokine Receptor gp130 physiology, Humans, Mice, Molecular Targeted Therapy, Receptors, Interleukin-6 antagonists & inhibitors, Scleroderma, Systemic drug therapy, Signal Transduction physiology, Fibrosis physiopathology, Interleukin-6 physiology, Receptors, Interleukin-6 physiology, Scleroderma, Systemic physiopathology, Wound Healing physiology
- Abstract
Interleukin-6 is a classic pro-inflammatory cytokine needed to mount an effective immune response. It is secreted by a wide array of cell types, however, its target cells are more restricted, due to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor. This therefore limits the amount of cells that can respond to IL-6. Transsignalling, the shedding of the membrane bound form of the IL-6 receptor (sIL-6R) into the local microenvironment, greatly increases the range of cells that can respond e.g. as part of a wound healing response necessary to restore the homeostatic balance. Therefore, tight regulation of IL-6 signalling must occur to stop an inappropriate wound healing response occurring. This review focusses on the role of IL-6 in inflammation and fibrosing conditions, with a particular emphasis on systemic sclerosis (SSc), a chronic autoimmune disease in which a classical hallmark of fibrosis occurs. This fibrosis, in particular the skin and internal organs, leads to contractures and internal organ failure respectively with potential fatal consequences. In this review we will discuss the biology of IL-6 in the context of fibrosing conditions such as SSc and argue why molecular targeting of IL-6 is a promising therapeutic target., (Copyright © 2012. Published by Elsevier Ltd.)
- Published
- 2012
- Full Text
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199. Cross-linked actin networks (CLANs) are present in lamina cribrosa cells.
- Author
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Job R, Raja V, Grierson I, Currie L, O'Reilly S, Pollock N, Knight E, and Clark AF
- Subjects
- Aged, Aged, 80 and over, Animals, Cattle, Cells, Cultured, Cross-Linking Reagents metabolism, Glaucoma, Open-Angle drug therapy, Humans, Microscopy, Confocal, Middle Aged, Actins metabolism, Antihypertensive Agents pharmacology, Dexamethasone pharmacology, Glaucoma, Open-Angle metabolism, Nerve Fibers metabolism, Optic Nerve metabolism
- Abstract
Aims: A study was undertaken to determine and compare the F-actin staining patterns in the cells of the lamina cribrosa (LC) of normal, dexamethasone (DEX)-treated and glaucomatous dissected tissue and cell cultures., Methods: About 30 dissected donor eyes and nine cell lines provided the human specimens; 25 eyes and 20 primary cell cultures provided the bovine material. Appropriate samples were exposed to 1×10⁻⁷ M DEX for up to 14 days. LC tissue and cells were stained with Phalloidin-Alexa 488 to identify F-actin, and all samples were examined by confocal or epifluorescent microscopy., Results: Both in the LC tissue and LC cell cultures the dominant actin arrangement was bundles of stress fibres. However, cross-linked actin networks (CLANs) were identified in the tissue and in culture. These were markedly increased by steroid treatment and were particularly large and abundant in cultures from glaucoma donors. CLANs were not associated with optic nerve head astrocytes., Conclusions: The presence of abundant stress fibres in situ and in vitro highlights the biomechanical contribution of LC cells. However, the identification of CLANs in these cells shows that they are not exclusive to the trabecular meshwork, the only other place they have been found, and may have a role in glaucoma pathology.
- Published
- 2010
- Full Text
- View/download PDF
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