Abstract
The proinflammatory cytokine IL-17A is considered a crucial player in rheumatoid arthritis (RA) pathogenesis. In experimental models of autoimmune arthritis, it has been suggested that the ...cellular source of IL-17A is CD4+ T cells (Th17 cells). However, little is known about the source of IL-17 in human inflamed RA tissue. We explored the cellular sources of IL-17A in human RA synovium. Surprisingly, only a small proportion of IL-17–expressing cells were T cells, and these were CCR6 negative. Unexpectedly, the majority of IL-17A expression colocalized within mast cells. Furthermore, we demonstrated in vitro that mast cells produced RORC-dependent IL-17A upon stimulation with TNF-α, IgG complexes, C5a, and LPS. These data are consistent with a crucial role for IL-17A in RA pathogenesis but suggest that in addition to T cells innate immune pathways particularly mediated via mast cells may be an important component of the effector IL-17A response.
MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related ...activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14⺠cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68⺠cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14⺠cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14⺠cells reduced TNF-α production. Finally, miR-155-deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.
Animal models of rheumatoid arthritis Asquith, Darren L; Miller, Ashley M; McInnes, Iain B ...
European journal of immunology,
August 2009, Volume:
39, Issue:
8
Journal Article
Peer reviewed
Open access
Animal models have been used extensively in studies of rheumatoid arthritis pathogenesis. Despite the inherent limitations of all animal models, several rodent models have significantly progressed ...our understanding of the fundamental mechanisms underpinning rheumatoid arthritis and contributed to several current major advances in treatment. These models include the induced arthritis models such as collagen-induced arthritis, collagen-antibody-induced arthritis, zymosan-induced arthritis, and the methylated BSA model, and the genetically manipulated or spontaneous arthritis models such as the TNF-α-transgenic mouse, K/BxN mouse, and the Skg mouse. Here, we describe these animal models and discuss their advantages and limitations.
Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1-like cytokine that signals via ...ST2, can reduce atherosclerosis development in ApoE(-/-) mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33-treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNgamma in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG(1), but decreased IgG(2a), which is consistent with a Th1-to-Th2 switch. IL-33-treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE(-/-) mice compared with control IgG-treated mice. Furthermore, coadministration of an anti-IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.
Stalking is one of the main types of abusive behaviour facilitated by technology. The purpose of the current study was twofold: to identify the challenges of cyberstalking investigations and ...prosecutions in Australia and determine how best to investigate these types of offences. A qualitative analysis of four years of interviews, focus groups and participant observations with police departments provides an overview of the cyberstalking investigative process. The findings map out the process from the initial report of the incident to the preparation of the prosecution brief. This analysis positions cyberstalking investigations as an interesting case study in the midst of increased scrutiny about the way that police investigate technology-facilitated abuse.
Background Idiopathic pulmonary fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to ...IPF; therefore, microRNAs may reveal novel pathogenic pathways. Objectives We sought to determine the regulatory role of microRNA (miR)-155 in the profibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts, and its contribution to experimental pulmonary fibrosis. Methods Bleomycin-induced lung fibrosis in wild-type and miR-155−/− mice was analyzed by histology, collagen, and profibrotic gene expression. Mechanisms were identified by in silico and molecular approaches and validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. Results miR-155−/− mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGF-β production, and activation of alternatively activated macrophages, contributed by deregulation of the miR-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the profibrotic phenotype of IPF and miR-155−/− fibroblasts. Conclusions We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.
RATIONALE:Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine interleukin (IL)-33 and its receptor ST2 are expressed in ...adipose tissue, but their role in adipose tissue inflammation during obesity is unclear.
OBJECTIVE:To examine the functional role of IL-33 in adipose tissues and investigate the effects on adipose tissue inflammation and obesity in vivo.
METHODS AND RESULTS:We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10) and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages toward an M2 alternatively activated phenotype (CD206), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed high-fat diet had increased body weight and fat mass and impaired insulin secretion and glucose regulation compared to WT controls fed high-fat diet.
CONCLUSIONS:In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity.
It is well established that violence and oppression towards vulnerable and marginalised communities are intensified and compounded during times of social upheaval, and the COVID-19 pandemic has ...exacerbated disablist and ableist violence against disabled people. During the first year of the pandemic, we have been confronted with instances of violence meted out to disabled subjects. In this article, we provide a theorisation of such violence. Based on an assemblage of our collective readings of Butler, Campbell and Young, as well as our own observations and experiences, we suggest that added anxieties currently confronting people's fragile corporeal embodiment are licensing abled subjects to violate disabled subjects to put them back in their place. Through an excavation of 'Norms, Binaries, and Anxieties', 'Abjection, Substitutability, and Disavowal', and 'Ableism and (Un)grievability', we trace the social contours of disablist and ableist violence, both within and beyond the context of the COVID-19 pandemic, and provide a way of imagining otherwise to resist this violence.
Given the import and impact of political campaign promises, this study systematically analyzed Donald Trump's campaign and rally speeches using a typology of verbal-textual hostility (V.T.H.) ...developed by Asquith (2013) from criminal hate incidents in the United Kingdom. Trump used all forms of V.T.H. previously identified by Asquith, except for sexualization, and new forms that may be specific to the political context. Analysis of speeches from 2015-2018 revealed that expatriation, criminalization, and domination were the most frequently used forms of V.T.H. deployed by Trump, which we consider in relation to the historical, social, and political context and consequences.
The psychological cost of exposure to traumatic events is receiving greater recognition in recent years, especially in terms of its impact in helping professions and emergency services. However, the ...costs to researchers remain relatively unexplored. In this article, we will discuss the nature and impact of vicarious trauma using two criminological research projects as case studies: one a qualitative project engaging with survivors of childhood sexual abuse, and the other, a quantitative analysis of police hate crime reports. In addition to considering the trauma elicited in fieldwork such as interviews, we interrogate the costs imposed on researchers during the coding and analysing processes. We suggest that the cost is potentially greater when the researcher has a personal connection with the issues being researched, but that this personal experience also provides the researcher with important skills for responding to new or compounded trauma. The costs of engagement with trauma may be compensated by the productive outputs and impact on policy and practice that this type of research may elicit. Understanding the impact and costs of engaging with close analyses of trauma is critical in developing more robust and ethical research processes to ensure that this trauma is appropriately managed so as to avert the long-term damage this work can inflict on researchers and participants.
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