10 results found
Joseph SR, Lum B, Banushi B, et al., 2020, Antibody/Ligand-Target Receptor Internalization Assay Protocol Using Fresh Human or Murine Tumor Ex Vivo Samples, STAR Protocols, Vol: 1, Pages: 100087-100087, ISSN: 2666-1667
Chew HY, De Lima PO, Cruz JLG, et al., 2020, Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies, CELL, Vol: 180, Pages: 895-+, ISSN: 0092-8674
Carson D, Barry R, Eve GD H, et al., 2020, Citrobacter rodentium induces rapid and unique metabolic and inflammatory responses in mice suffering from severe disease, Cellular Microbiology, Vol: 22, Pages: 1-17, ISSN: 1462-5814
The mouse pathogen Citrobacter rodentium is used to model infections with enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC). Pathogenesis is commonly modelled in mice developing mild disease (e.g., C57BL/6). However, little is known about host responses in mice exhibiting severe colitis (e.g., C3H/HeN), which arguably provide a more clinically relevant model for human paediatric enteric infection. Infection of C3H/HeN mice with C. rodentium results in rapid colonic colonisation, coinciding with induction of key inflammatory signatures and colonic crypt hyperplasia. Infection also induces dramatic changes to bioenergetics in intestinal epithelial cells, with transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis and higher abundance of SGLT4, LDHA, and MCT4. Concomitantly, mitochondrial proteins involved in the TCA cycle and OXPHOS were in lower abundance. Similar to observations in C57BL/6 mice, we detected simultaneous activation of cholesterol biogenesis, import, and efflux. Distinctly, however, the pattern recognition receptors NLRP3 and ALPK1 were specifically induced in C3H/HeN. Using cell‐based assays revealed that C. rodentium activates the ALPK1/TIFA axis, which is dependent on the ADP‐heptose biosynthesis pathway but independent of the Type III secretion system. This study reveals for the first time the unfolding intestinal epithelial cells' responses during severe infectious colitis, which resemble EPEC human infections.
Barry R, Ruano-Gallego D, Radhakrishnan ST, et al., 2020, Faecal neutrophil elastase-antiprotease balance reflects colitis severity, Mucosal Immunology, Vol: 13, Pages: 322-333, ISSN: 1933-0219
Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.
Mullineaux-Sanders C, Sanchez-Garrido J, Hopkins EGD, et al., 2019, Citrobacter rodentium-host-microbiota interactions: immunity, bioenergetics and metabolism, NATURE REVIEWS MICROBIOLOGY, Vol: 17, Pages: 701-715, ISSN: 1740-1526
Joseph SR, Gaffney D, Barry R, et al., 2019, An Ex Vivo Human Tumor Assay Shows Distinct Patterns of EGFR Trafficking in Squamous Cell Carcinoma Correlating to Therapeutic Outcomes, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 139, Pages: 213-223, ISSN: 0022-202X
Barry R, John SW, Liccardi G, et al., 2018, SUMO-mediated regulation of NLRP3 modulates inflammasome activity, Nature Communications, Vol: 9, ISSN: 2041-1723
The NLRP3 inflammasome responds to infection and tissue damage, and rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. How the NLRP3 inflammasome is negatively regulated is poorly understood. Here we show that NLRP3 inflammasome activation is suppressed by sumoylation. NLRP3 is sumoylated by the SUMO E3-ligase MAPL, and stimulation-dependent NLRP3 desumoylation by the SUMO-specific proteases SENP6 and SENP7 promotes NLRP3 activation. Defective NLRP3 sumoylation, either by NLRP3 mutation of SUMO acceptor lysines or depletion of MAPL, results in enhanced caspase-1 activation and IL-1β release. Conversely, depletion of SENP7 suppresses NLRP3-dependent ASC oligomerisation, caspase-1 activation and IL-1β release. These data indicate that sumoylation of NLRP3 restrains inflammasome activation, and identify SUMO proteases as potential drug targets for the treatment of inflammatory diseases.
Plaza-Menacho I, Barnouin K, Barry R, et al., 2016, RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements, Cell Reports, Vol: 17, Pages: 3319-3332, ISSN: 2211-1247
Hill MM, Daud NH, Aung CS, et al., 2012, Co-Regulation of Cell Polarization and Migration by Caveolar Proteins PTRF/Cavin-1 and Caveolin-1, PLOS ONE, Vol: 7, ISSN: 1932-6203
Ashe A, Butterfield NC, Town L, et al., 2012, Mutations in mouse Ift144 model the craniofacial, limb and rib defects in skeletal ciliopathies, HUMAN MOLECULAR GENETICS, Vol: 21, Pages: 1808-1823, ISSN: 0964-6906
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.