6 results on '"Graham, Gerard J."'
Search Results
2. Sustained exposure to systemic endotoxin triggers chemokine induction in the brain followed by a rapid influx of leukocytes
- Author
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Thomson, Carolyn A., McColl, Alison, Graham, Gerard J., and Cavanagh, Jonathan
- Published
- 2020
- Full Text
- View/download PDF
3. TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain.
- Author
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McColl, Alison, Thomson, Carolyn A., Nerurkar, Louis, Graham, Gerard J., and Cavanagh, Jonathan
- Subjects
TOLL-like receptors ,CELL receptors ,SKIN inflammation ,CHEMOKINE receptors ,CHEMOKINES ,LEUCOCYTES ,BRAIN ,RNA metabolism ,BRAIN metabolism ,ANIMAL experimentation ,ANIMALS ,ANTIGENS ,BIOLOGICAL models ,IMMUNOMODULATORS ,CARCINOGENS ,CELL physiology ,FLOW cytometry ,MICE ,NERVE tissue proteins ,NEUROPEPTIDES ,QUINOLINE ,OLIGONUCLEOTIDE arrays ,MEMBRANE glycoproteins ,GENE expression profiling - Abstract
Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders.Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation-imiquimod-to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour.Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity.Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response. [ABSTRACT FROM AUTHOR]- Published
- 2016
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4. Peripheral inflammation is associated with remote global gene expression changes in the brain.
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Thomson, Carolyn A., McColl, Alison, Cavanagh, Jonathan, and Graham, Gerard J.
- Subjects
GENE expression ,CYTOKINES ,NATURAL immunity ,INTERFERONS ,LIPOPOLYSACCHARIDES ,TOLL-like receptors ,CENTRAL nervous system - Abstract
Background Although the central nervous system (CNS) was once considered an immunologically privileged site, in recent years it has become increasingly evident that cross talk between the immune system and the CNS does occur. As a result, patients with chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease or psoriasis, are often further burdened with neuropsychiatric symptoms, such as depression, anxiety and fatigue. Despite the recent advances in our understanding of neuroimmune communication pathways, the precise effect of peripheral immune activation on neural circuitry remains unclear. Utilizing transcriptomics in a well-characterized murine model of systemic inflammation, we have started to investigate the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Methods Several different systemic and tissue-specific models of peripheral toll-like-receptor-(TLR)- driven (lipopolysaccharide (LPS), lipoteichoic acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and 12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in C57BL/6 mice. Whole brain transcriptional profiles were assessed and compared 48 hours after intraperitoneal injection of lipopolysaccharide or vehicle, using Affymetrix GeneChip microarrays. Target gene induction, identified by microarray analysis, was validated independently using qPCR. Expression of the same panel of target genes was then investigated in a number of sterile and other TLR-dependent models of peripheral inflammation. Results Microarray analysis of whole brains collected 48 hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain. In addition to acute LPS challenge, ISGs were induced in the brain following both chronic LPS-induced systemic inflammation and Imiquimod-induced skin inflammation. Unique to the brain, this transcriptional response is indicative of peripherally triggered, interferon-mediated CNS inflammation. Similar models of sterile inflammation and lipoteichoic-acid-induced systemic inflammation did not share the capacity to trigger ISG induction in the brain. Conclusions These data highlight ISG induction in the brain as being a consequence of a TLR-induced type I interferon response. As considerable evidence links type I interferons to psychiatric disorders, we hypothesize that interferon production in the brain could represent an important mechanism, linking peripheral TLR-induced inflammation with behavioural changes. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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5. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD.
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Mori, Michiko, Andersson, Cecilia K., Graham, Gerard J., Löfdahl, Claes-Göran, and Erjefält, Jonas S.
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OBSTRUCTIVE lung diseases patients ,BRONCHIOLES ,PULMONARY function tests ,LYMPHATICS ,SCAVENGER receptors (Biochemistry) - Abstract
Background: De novo lymphatic vessel formation has recently been observed in lungs of patients with moderate chronic obstructive pulmonary disease (COPD). However, the distribution of lymphatic vessel changes among the anatomical compartments of diseased lungs is unknown. Furthermore, information regarding the nature of lymphatic vessel alterations across different stages of COPD is missing. This study performs a detailed morphometric characterization of lymphatic vessels in major peripheral lung compartments of patients with different severities of COPD and investigates the lymphatic expression of molecules involved in immune cell trafficking. Methods: Peripheral lung resection samples obtained from patients with mild (GOLD stage I), moderate-severe (GOLD stage II-III), and very severe (GOLD stage IV) COPD were investigated for podoplanin-immunopositive lymphatic vessels in distinct peripheral lung compartments: bronchioles, pulmonary blood vessels and alveolar walls. Control subjects with normal lung function were divided into never smokers and smokers. Lymphatics were analysed by multiple morphological parameters, as well as for their expression of CCL21 and the chemokine scavenger receptor D6. Results: The number of lymphatics increased by 133% in the alveolar parenchyma in patients with advanced COPD compared with never-smoking controls (p < 0.05). In patchy fibrotic lesions the number of alveolar lymphatics increased 20-fold from non-fibrotic parenchyma in the same COPD patients. The absolute number of lymphatics per bronchiole and artery was increased in advanced COPD, but numbers were not different after normalization to tissue area. Increased numbers of CCL21- and D6-positive lymphatics were observed in the alveolar parenchyma in advanced COPD compared with controls (p < 0.01). Lymphatic vessels also displayed increased mean levels of immunoreactivity for CCL21 in the wall of bronchioles (p < 0.01) and bronchiole-associated arteries (p < 0.05), as well as the alveolar parenchyma (p < 0.001) in patients with advanced COPD compared with never-smoking controls. A similar increase in lymphatic D6 immunoreactivity was observed in bronchioles (p < 0.05) and alveolar parenchyma (p < 0.01). Conclusions: This study shows that severe stages of COPD is associated with increased numbers of alveolar lymphatic vessels and a change in lymphatic vessel phenotype in major peripheral lung compartments. This novel histopathological feature is suggested to have important implications for distal lung immune cell traffic in advanced COPD. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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6. A murine specific expansion of the Rhox cluster involved in embryonic stem cell biology is under natural selection.
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Jackson, Melany, Watt, Alistair J, Gautier, Philippe, Gilchrist, Derek, Driehaus, Johanna, Graham, Gerard J, Keebler, Jon, Prugnolle, Franck, Awadalla, Philip, and Forrester, Lesley M
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GENETICS ,EMBRYONIC stem cells ,X chromosome ,NATURAL selection ,TRANSCRIPTION factors - Abstract
Background: The rodent specific reproductive homeobox (Rhox) gene cluster on the X chromosome has been reported to contain twelve homeobox-containing genes, Rhox1-12. Results: We have identified a 40 kb genomic region within the Rhox cluster that is duplicated eight times in tandem resulting in the presence of eight paralogues of Rhox2 and Rhox3 and seven paralogues of Rhox4. Transcripts have been identified for the majority of these paralogues and all but three are predicted to produce full-length proteins with functional potential. We predict that there are a total of thirty-two Rhox genes at this genomic location, making it the most gene-rich homoeobox cluster identified in any species. From the 95% sequence similarity between the eight duplicated genomic regions and the synonymous substitution rate of the Rhox2, 3 and 4 paralogues we predict that the duplications occurred after divergence of mouse and rat and represent the youngest homoeobox cluster identified to date. Molecular evolutionary analysis reveals that this cluster is an actively evolving region with Rhox2 and 4 paralogues under diversifying selection and Rhox3 evolving neutrally. The biological importance of this duplication is emphasised by the identification of an important role for Rhox2 and Rhox4 in regulating the initial stages of embryonic stem (ES) cell differentiation. Conclusion: The gene rich Rhox cluster provides the mouse with significant biological novelty that we predict could provide a substrate for speciation. Moreover, this unique cluster may explain species differences in ES cell derivation and maintenance between mouse, rat and human. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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